Objective:To explore the application effect of combined exercise intervention based on the hospital-community-family model on intrinsic capacity in elderly patients with diabetes mellitus complicated by chronic kidney...Objective:To explore the application effect of combined exercise intervention based on the hospital-community-family model on intrinsic capacity in elderly patients with diabetes mellitus complicated by chronic kidney disease.Methods:Using convenience sampling,100 elderly patients with diabetes mellitus complicated by chronic kidney disease who received treatment in the endocrinology department of a tertiary A-level hospital from May 2024 to May 2025 were selected as the study subjects.They were randomly divided into an experimental group(50 cases)and a control group(50 cases)using a random number table method.The control group received routine health education and telephone follow-up,while the experimental group,in addition to the control group’s interventions,underwent combined exercise intervention based on the hospital-community-family model.Remote medical guidance was utilized to monitor and study the application effect of exercise intervention on intrinsic capacity in elderly patients with diabetes mellitus complicated by chronic kidney disease.Fasting blood glucose,2-hour postprandial blood glucose,glomerular filtration rate,6-minute walk distance,and scores in five dimensions of intrinsic capacity(exercise,cognition,psychology,vitality,and sensation)were measured before the intervention,at 4 weeks of intervention,and at 12 weeks of intervention for both groups.Results:Before the exercise intervention,there were no statistically significant differences(p>0.05)between the two groups in terms of fasting blood glucose,2-hour postprandial blood glucose,glomerular filtration rate,6-minute walk distance,and scores across five dimensions of intrinsic capacity:mobility,cognition,psychology,vitality,and sensation.After 12 weeks of intervention,the experimental group demonstrated significantly higher scores than the control group in glomerular filtration rate,6-minute walk distance,and the dimensions of mobility,cognition,and vitality within intrinsic capacity,with all differences being statistically significant(p<0.05).Conversely,the experimental group showed significantly lower scores than the control group in fasting blood glucose,2-hour postprandial blood glucose,and the psychological dimension of intrinsic capacity,with these differences also being statistically significant(p<0.05).Conclusion:Continuous nursing care utilizing telemedicine based on a hospital-community-family model combined with exercise intervention can effectively enhance exercise tolerance and intrinsic capacity in elderly patients with diabetes mellitus complicated by chronic kidney disease,thereby improving their quality of life.The effectiveness of the intervention is positively correlated with the duration of the intervention.展开更多
Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that M...Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.展开更多
BACKGROUND Diabetic kidney disease(DKD)has become the leading cause of end-stage renal disease.The disease characteristics,morbidity,and renal function progression rate of patients with DKD are all related to sex.This...BACKGROUND Diabetic kidney disease(DKD)has become the leading cause of end-stage renal disease.The disease characteristics,morbidity,and renal function progression rate of patients with DKD are all related to sex.This suggests that sex hormones may play an important role in changing renal function in patients with diabetes.There have been only a few studies on the correlation between sex hormones and DKD,which have contradictory conclusions.AIM To investigate the relationship between circulating sex hormone levels and DKD in men and postmenopausal women with type 2 diabetes mellitus(T2DM).METHODS This retrospective cross-sectional study included 356 patients with T2DM.Pearson or Spearman rank correlation analyses assessed the relationships between sex hormone levels and renal function indices.By adjusting for age,body mass index,systolic blood pressure,diastolic blood pressure,duration of diabetes,use of sodium-glucose cotrasporter-2 inhibitor,use of glucagon-like peptide-1 receptor agonist,hypertension,use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor,diabetic retinopathy,diabetic peripheral vascular disease,triglyceride,uric acid,and hemoglobin A1c,multiple linear regression and logistic regression analyses were conducted to identify factors influencing the urinary albumin/creatinine ratio(UACR)and DKD.RESULTS In men,dehydroepiandrosterone sulfate levels were inversely associated with log-transformed UACR after adjustment for covariate factors[regression coefficient(β)=-0.691,95%confidence interval(CI):-1.241 to-0.141 for quartile 4 vs quartile 1;P=0.006 for trend].Elevated levels of estradiol were positively associated with DKD[odds ratio(OR)=3.097,95%CI:1.083-8.856 for quartile 4 vs quartile 1;P=0.041 for trend],and higher luteinizing hormone(LH)levels were similarly associated with DKD(OR=4.164,95%CI:1.30-13.330 for quartile 4 vs quartile 1;P=0.048 for trend).In postmenopausal women,LH levels were positively correlated with log-transformed UACR and DKD(β=1.039,95%CI:0.284-1.794 for quartile 4 vs quartile 1;P=0.006 for trend and OR=15.117,95%CI:2.191-104.326 for quartile 4 vs quartile 1;P=0.004 for trend).Follicle-stimulating hormone(FSH)levels were also positively associated with DKD(OR=9.588,95%CI:1.680-54.709 for quartile 4 vs quartile 1;P=0.014 for trend).CONCLUSION In men with T2DM,elevated levels of estradiol and LH levels were positively associated with increased risk of DKD.In postmenopausal women with T2DM,high FSH and LH levels were positively associated with increased risk of DKD.展开更多
BACKGROUND The progression of diabetic kidney disease(DKD)affects the patient’s kidney glomeruli and tubules,whose normal functioning is essential for maintaining normal calcium(Ca)and phosphorus(P)metabolism in the ...BACKGROUND The progression of diabetic kidney disease(DKD)affects the patient’s kidney glomeruli and tubules,whose normal functioning is essential for maintaining normal calcium(Ca)and phosphorus(P)metabolism in the body.The risk of developing osteoporosis(OP)in patients with DKD increases with the aggravation of the disease,including a higher risk of fractures,which not only affects the quality of life of patients but also increases the risk of death.AIM To analyze the risk factors for the development of OP in patients with DKD and their correlation with Ca-P metabolic indices,fibroblast growth factor 23(FGF23),and Klotho.METHODS One hundred and fifty-eight patients with DKD who were admitted into the Wuhu Second People’s Hospital from September 2019 to May 2021 were selected and divided into an OP group(n=103)and a normal bone mass group(n=55)according to their X-ray bone densitometry results.Baseline data and differences in Ca-P biochemical indices,FGF23,and Klotho were compared.The correlation of Ca-P metabolic indices with FGF23 and Klotho was discussed,and the related factors affecting OP in patients with DKD were examined by multivariate logistic regression analysis.RESULTS The OP group had a higher proportion of females,an older age,and a longer diabetes mellitus duration than the normal group(all P<0.05).Patients in the OP group exhibited significantly higher levels of intact parathyroid hormone(iPTH),blood P,Ca-P product(Ca×P),fractional excretion of phosphate(FeP),and FGF23,as well as lower estimated glomerular filtration rate,blood Ca,24-hour urinary phosphate excretion(24-hour UPE),and Klotho levels(all P<0.05).In the OP group,25-(OH)-D3,blood Ca,and 24-hour UPE were negatively correlated with FGF23 and positively correlated with Klotho.In contrast,iPTH,blood Ca,Ca×P,and FeP exhibited a positive correlation with FGF23 and an inverse association with Klotho(all P<0.05).Moreover,25-(OH)-D3,iPTH,blood Ca,FePO4,FGF23,Klotho,age,and female gender were key factors that affected the lumbar and left femoral neck bone mineral density.CONCLUSION The Ca-P metabolism metabolic indexes,FGF23,and Klotho in patients with DKD are closely related to the occurrence and development of OP.展开更多
Objective Diabetic kidney disease is a serious complication of diabetes,which is the leading cause of end-stage renal disease worldwide.Approximately 40%of individuals with diabetes develop diabetic kidney disease.At ...Objective Diabetic kidney disease is a serious complication of diabetes,which is the leading cause of end-stage renal disease worldwide.Approximately 40%of individuals with diabetes develop diabetic kidney disease.At present,the most important drugs for diabetic kidney disease include renin-angiotensin-aldosterone system inhibitors,angiotensin receptor blockers,sodium-glucose cotransporter-2 inhibitors,and newly approved aldosterone receptor antagonists.However,to date,there are still no effective drugs to prevent diabetic kidney disease from progressing to end-stage renal disease.Network pharmacology combined with bioinformatics and pharmacology provides a powerful tool for studying the mechanism of drug action.Traditional Chinese medicine has accumulated rich experience in the treatment of diabetic kidney disease,and its multi-target,multi-component,and multi-pathway characteristics provide new ideas for modern medicine.This article reviews the research progress of network pharmacology and drug therapy in diabetic kidney disease.展开更多
Diabetes mellitus entails significant health problems worldwide.The pathogenesis of diabetes is multifactorial,resulting from interactions of both genetic and environmental factors that trigger a complex network of pa...Diabetes mellitus entails significant health problems worldwide.The pathogenesis of diabetes is multifactorial,resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events,with metabolic and hemodynamic alterations.In this context,inflammation has emerged as a key pathophysiology mechanism.New pathogenic pathways will provide targets for prevention or future treatments.This review will focus on the implications of inflammation in diabetes mellitus,with special attention to inflammatory cytokines.展开更多
Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal ste...Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal stem cells(MSCs)have shown great promise in tissue regeneration for DKD treatment and have protective effects against DKD,including decreased blood glucose and urinary protein levels and improved renal function.MSCs can directly differ-entiate into kidney cells or act via paracrine mechanisms to reduce apoptosis in DKD by modulating signaling pathways.MSC-derived extracellular vesicles(MSC-EVs)mitigate apoptosis and DKD-related symptoms by transferring miRNAs to target cells or organs.However,studies on the regulatory mechanisms of MSCs and MSC-EVs in apoptosis in DKD are insufficient.This review compre-hensively examines the mechanisms of apoptosis in DKD and research progress regarding the roles of MSCs and MSC-EVs in the disease process.展开更多
Diabetes mellitus is one of the most common causes of chronic kidney disease.Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria an...Diabetes mellitus is one of the most common causes of chronic kidney disease.Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure.The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments,such as the vascular system and glomeruli.Glomerular alterations include thickening of the glomerular basement membrane,loss of podocytes,and segmental mesangiolysis,which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules.Beyond lesions directly related to diabetes,awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing.These nondiabetic lesions include focal segmental glomerulosclerosis,IgA nephropathy,and other primary or secondary renal disorders.Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches.However,the relationship between diabetes and the kidney is bidirectional;thus,new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases.Here,we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course,differential diagnosis,and therapeutic opportunities offered by novel drugs.展开更多
Background: Worldwide, diabetic nephropathy-DN is the leading cause of end-stage kidney disease-ESKD, DN is a common cause of renal failure with a reported frequency of 10% - 15% in type-2-diabetes-mellitus-T2DM patie...Background: Worldwide, diabetic nephropathy-DN is the leading cause of end-stage kidney disease-ESKD, DN is a common cause of renal failure with a reported frequency of 10% - 15% in type-2-diabetes-mellitus-T2DM patients, however there is a great discrepancy between countries. The aim of the pre-sent study is to evaluate the findings of kidney biopsies performed on diabetic patients. Materials and Methods: We studied native kidney histopathological findings in the period from January 2016 till end of December 2018 done for patients with T2DM with chronic kidney diseases-CKD. Results: A total of 82 DM-patients, 50 males (61%) and 32 females (39%) with age mean (95% CI) of 50.8 (47.1 - 55.2) years for all patients, ranged between 15 to 65 years. Histological findings showed that 57.3% of patients had DN. While focal-segmental-glomerulosclerosis-FSGS was present in 20.7%—primary in 8.6% and secondary in 12.1%. IgA represented 4.9%, while Lupus nephritis, Membranous and drug induced interstitial nephritis were each present in 3.7%. MCD was present in 2.4%. Lastly diffuse proliferative GN, ANCA associated glomerulonephritis, and hypertensive nephrosclerosis accounted for 1.2%. Conclusion: The prevalence of NDKD is remarkably frequent in DM patients who underwent kidney biopsy and FSGS was the most frequent diagnosis. To get a proper histopathological diagnosis, an adequate tissue biopsy is needed with an adequate number of glomeruli. There is a great need for more consideration to biopsy diabetic patients, as the finding of NDKD requires a different therapeutic approach. This, hopefully, will help to manage these patients better and therefore, ameliorate the progression to ESKD over time and therefore delay the need for RRT.展开更多
Objective Immune infiltration and ferroptosis play pivotal roles in the progression of diabetic kidney disease(DKD).However,investigations of immune cell-related ferroptosis genes(ICRFGs)in the context of DKD are insu...Objective Immune infiltration and ferroptosis play pivotal roles in the progression of diabetic kidney disease(DKD).However,investigations of immune cell-related ferroptosis genes(ICRFGs)in the context of DKD are insufficient.This study aimed to identify ICRFGs relevant to DKD and screen related inhibitors.Methods In this study,two DKD datasets from the GEO database were utilized.We adopted the ESTIMATE algorithm to generate microenvironment scores.The CIBERSORT and WGCNA methods were employed to identify immune-related differentially expressed genes(DEGs).The common ICRFGs were derived through a Venn diagram.We employed random forest,LASSO,K-M survival,receiver operating characteristic(ROC)curve,clinical relevance,and Spearman correlation analyses to select hub ICRFGs further.Immunohistochemical experiments were also performed to validate the expression.Additionally,we utilized the Selleck database to obtain ferroptosis-related compounds and used USCF Chimera 1.14 to minimize energy,combined with molecular dynamics(MD)simulations to explore possible ferroptosis inhibitors.Results Immunohistochemical analysis revealed that arachidonate 5-lipoxygenase(ALOX5)was significantly highly expressed in the db/db group.Clinical correlation and K-M survival analyses confirmed ALOX5 as the most crucial ICRFG in DKD.Furthermore,ALOX5 was significantly enriched in the terms ECM-receptor interaction,regulation of chemokine production,and regulation of the inflammatory response.A positive correlation was observed between ALOX5 and M1 macrophages,γδT cells,and monocytes.Moreover,virtual screening and MD revealed NSC348884,salvianolic acid B,and deltarasin as potential ferroptosis inhibitors in combination with ALOX5.Conclusion We identified ALOX5 as a reliable and prospective diagnostic marker associated with immunity and ferroptosis in DKD patients.展开更多
BACKGROUND Injury to the glomerular filtration barrier causes diabetic kidney disease(DKD),and glomerular endothelial-mesenchymal transition damages the filtration barrier of glomerular endothelial cells.Shenfushu gra...BACKGROUND Injury to the glomerular filtration barrier causes diabetic kidney disease(DKD),and glomerular endothelial-mesenchymal transition damages the filtration barrier of glomerular endothelial cells.Shenfushu granules(SFSGs)can treat chronic renal failure;however,their role and mechanism in DKD remain unclear.AIM To investigate the role of SFSGs in delaying DKD progression and their underlying mechanism in a streptozotocin-induced DKD mouse model.METHODS The microalbumin content in the urine and the blood glucose,creatinine,and blood urea nitrogen levels in the serum were measured.The expression and distribution ofα-smooth muscle actin(α-SMA),heparan sulfate(HS)and cluster of differentiation(CD)31 were observed through immunofluorescence or immunohistochemistry.Western blotting was conducted to measure the expression of CD31,α-SMA,PIK3R1,protein kinase B(AKT),phospho-PIK3R1,phospho-AKT,and heparanase-1.Network pharmacology was conducted to screen and identify the core components and targets of SFSGs.Molecular docking and dynamic simulations were performed to evaluate the binding ability of the core components of SFSGs to their core targets.RESULTS Compared with those in the model group,the 24-hour microalbuminuria(188.2±20.1 and 140.4±24.7 vs 323.2±44.4),serum creatinine(79.4±2.6 and 68.7±6.0 vs 110.2±4.8),blood urea nitrogen(14.4±1.1 and 13.1±0.5 vs 19.5±1.1),and renal index(20.3±1.0 and 19.6±0.8 vs 25.3±1.7)were significantly lower in the SFSGs(2.08 and 4.16 g/kg/day extract)-treated DKD mice.SFSGs inhibited the down regulation of CD31 and the upregulation ofα-SMA in the glomerular endothelial cells of DKD mice.Additionally,SFSGs suppressed the decrease in glycocalyx thickness and the expression of its component HS.Network pharmacology revealed that PIK3R1 was the core target of SFSGs.SFSGs markedly downregulate the expression of phospho-PIK3R1,phospho-AKT,and heparanase-1.However,the PIK3R1 agonist abolished the regulatory effect of SFSGs on the expression of CD31,α-SMA,and heparanase-1.CONCLUSION Collectively,these results suggest that SFSGs can significantly delay DKD progression and inhibit injury to the glycocalyx and the endothelial-mesenchymal transition of glomerular endothelial cells.This mechanism is related to PIK3R1/AKT/heparanase-1 signaling pathway regulation.展开更多
Diabetic kidney disease(DKD),a primary cause of end-stage renal disease,results from progressive tissue remodeling and loss of kidney function.While single-cell RNA sequencing has significantly accelerated our underst...Diabetic kidney disease(DKD),a primary cause of end-stage renal disease,results from progressive tissue remodeling and loss of kidney function.While single-cell RNA sequencing has significantly accelerated our understanding of cellular diversity and dynamics in DKD,its lack of spatial resolution limits insights into tissue-specific dysregulation and the microenvironment.Spatial transcriptomics(ST)is an innovative technology that combines gene expression with spatial localization,offering a powerful approach to dissect the molecular mechanisms of DKD.This mini-review introduces how ST has transformed DKD research by enabling spatially resolved analysis of cell interactions and identifying localized molecular alterations in glomeruli and tubules.ST has revealed dynamic intercellular communication within the renal microenvironment,lesion-specific gene expression patterns,and immune infiltration profiles.For example,SlideseqV2 has highlighted disease-specific cellular neighborhoods and associated signaling networks.Furthermore,ST has pinpointed key genes implicated in disease progression,such as fibrosis-related proteins and transcription factors in tubular damage.By integration of ST with computational tools such as machine learning and network-based analysis can help uncover gene regulatory mechanisms and potential therapeutic targets.However,challenges remain in limited spatial resolution,high data complexity,and computational demands.Addressing these limitations is essential for advancing precision medicine in DKD.展开更多
OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-...OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.展开更多
Objective:To investigate the effects of Alpiniae oxyphyllae Fructus(AOF)on renal lipid deposition in diabetic kidney disease(DKD)and elucidate its molecular mechanisms.Methods:The mechanism of AOF in treating DKD was ...Objective:To investigate the effects of Alpiniae oxyphyllae Fructus(AOF)on renal lipid deposition in diabetic kidney disease(DKD)and elucidate its molecular mechanisms.Methods:The mechanism of AOF in treating DKD was explored by network pharmacological enrichment analysis,molecular docking,and molecular dynamics simulation.The effects of AOF on renal function and lipid deposition were assessed in a mouse model of DKD and high glucose-stressed HK-2 cells.Cell viability and lipid accumulation were detected by CCK8 and oil red O staining.The expressions of PPARαand fatty acid oxidation-related genes(ACOX1 and CPT1A)were detected by quantitative RT-PCR,Western blot,and immunofluorescence.Furthermore,PPARαknockdown was performed to examine the molecular mechanism of AOF in treating DKD.Results:Network pharmacological enrichment analysis,molecular docking,and molecular dynamics simulation showed that the active compounds in AOF targeted PPARαand thus transcriptionally regulated ACOX1 and CPT1A.AOF lowered blood glucose,improved dyslipidemia,and attenuated renal injury in DKD mice.AOF-containing serum accentuated high glucose-induced decrease in cell viability and ameliorated lipid accumulation.Additionally,it significantly upregulated the expression of PPARα,ACOX1,and CPT1A in both in vivo and in vitro experiments,which was reversed by PPARαknockdown.Conclusions:AOF may promote fatty acid oxidation via PPARαto ameliorate renal lipid deposition in DKD.展开更多
BACKGROUND Diabetic kidney disease(DKD)stands as the key contributor to chronic kidney disease worldwide.Clinical studies have shown that Kunkui Baoshen decoction(KKBS)effectively reduces proteinuria and enhances rena...BACKGROUND Diabetic kidney disease(DKD)stands as the key contributor to chronic kidney disease worldwide.Clinical studies have shown that Kunkui Baoshen decoction(KKBS)effectively reduces proteinuria and enhances renal function in DKD patients.However,its precise molecular targets and therapeutic mechanisms remain to be thoroughly clarified.AIM To evaluate the nephroprotective efficacy of KKBS in DKD and explore the underlying mechanisms of action.METHODS Liquid chromatography-tandem mass spectrometry was utilized to analyze the chemical constituents of KKBS.Metabonomic and transcriptomic analyses were conducted to identify key targets and pathways associated with the therapeutic effects of KKBS on DKD.The nephroprotective effects of KKBS were assessed both in high glucose-induced human kidney-2 cells and in db/db mice.A variety of assays were performed,including Cell Counting Kit-8,Western blot,quantitative reverse transcription-polymerase chain reaction,immunofluorescence,coimmunoprecipitation,periodic acid-Schiff staining,Masson staining,hematoxylin and eosin staining,immunohistochemistry,and mitochondrial morphology analysis.RESULTS The glutathione metabolic pathway emerged as the most prominent metabolic pathway in the metabonomic analysis of KKBS.Transcriptomic and bioinformatic analyses revealed that nuclear receptor coactivator 4(NCOA4)was instrumental in regulating ferroptosis within renal tubules of mice with DKD.Both in vitro and in vivo experiments showed that KKBS ameliorated renal dysfunction,mitigated renal tissue damage,and repressed the expression of autophagy-dependent ferroptosis markers and inflammatory fibrosis.Mechanistically,KKBS enhanced the interaction between the homologous to E6-AP C-terminus and RCC1-like domaincontaining E3 ubiquitin protein ligase(HERC2)and NCOA4,leading to K48-related ubiquitination and subsequent degradation of NCOA4.This process inhibited autophagy-dependent ferroptosis,reduced the release of pro-fibrotic inflammatory factors,and ultimately exerted an anti-fibrotic effect in DKD.CONCLUSION KKBS confers nephroprotection in DKD by modulating HERC2/NCOA4-mediated autophagy-dependent ferroptosis,thereby alleviating renal fibrosis.展开更多
One of the most prevalent long-term effects of diabetes is diabetic kidney disease(DKD),which is linked to problems with the metabolism of amino acids,fats,and carbohydrates.The fundamental pathogenic mechanisms of DK...One of the most prevalent long-term effects of diabetes is diabetic kidney disease(DKD),which is linked to problems with the metabolism of amino acids,fats,and carbohydrates.The fundamental pathogenic mechanisms of DKD cannot be adequately treated by current clinical medicines;they can only slow the illness’s progression to end-stage renal disease.We will concentrate on integrating human umbilical cord mesenchymal stem cell(hUC-MSC)-related mechanisms and potential applications into the therapy of DKD,as this work shows that hUCMSCs can be used to treat metabolic liver obesity associated with diabetes.Future studies on the connection between hUC-MSCs and related illnesses ought to be promoted.展开更多
The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney ...The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney disease.However,novel therapies,particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide-1(GLP-1)receptor agonists,which were initially developed for hyperglycemia management,have transformed the treatment of obesity,heart failure,cardiovascular disease,and more recently,DKD.SGLT2 inhibitors have consistently and significantly reduced cardiovascular events,albuminuria,and glomerular filtration rate,highlighting their efficacy across diverse clinical presentations for patients with kidney impairment.Although fewer studies have specifically investigated GLP-1 receptor agonists in patients with kidney disease,existing evidence underscores their potential to slow renal disease progression,reduce albuminuria,and improve clinically relevant outcomes.However,further research is needed to better identify patients most likely to benefit from treatment.Together,these therapies represent valuable advancements for DKD,offering significant reductions in morbidity and mortality and shifting the management of the disease by becoming essential pillars for the treatment of these patients.展开更多
Objective To predict the autophagy-related pathogenesis and key diagnostic genes of diabetic kidney disease(DKD)through bioinformatics analysis,and to identify related Chinese medicines.Methods Data from sequencing mi...Objective To predict the autophagy-related pathogenesis and key diagnostic genes of diabetic kidney disease(DKD)through bioinformatics analysis,and to identify related Chinese medicines.Methods Data from sequencing microarrays GSE30528,GSE30529,and GSE1009 in the Gene Expression Omnibus(GEO)were employed.Differentially expressed genes(DEGs)with adjusted P<0.05 from GSE30528 and GSE30529 were identified.Combining these DEGs with the human autophagy gene database,Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses,and protein-protein interaction(PPI)network analysis were conducted on the obtained DKD autophagy-related genes.Subsequently,the least absolute shrinkage and selection operator(LASSO)regression and support vector machinerecursive feature elimination(SVM-RFE)algorithms were adopted to select autophagy-related genes.The diagnostic capability of these genes was assessed through analysis with the external validation set from microarray GSE1009,and relevant Chinese medicines were inversely predicted using the SymMap database.Results A total of 2014 DEGs were selected from GSE30528 and GSE30529,leading to the identification of 37 DKD autophagy-related genes.GO analysis indicated 681 biological mechanisms,including autophagy regulation and plasma membrane microdomain activity.KEGG enrichment analysis identified 112 related signaling pathways.PPI network analysis showed a marked enrichment of autophagy-related genes in DKD.Through LASSO regression and SVM-RFE,four core diagnostic genes for autophagy in DKD were identified:protein phosphatase 1 regulatory subunit 15A(PPP1R15A),hypoxia inducible factor 1 alpha subunit(HIF1α),deleted in liver cancer 1(DLC1),and ceroid lipofuscinosis neuronal 3(CLN3).The external validation set demonstrated high diagnostic efficiency for these genes.Finally,146 kinds of potential Chinese medicines were predicted using the SymMap database,with heatclearing and detoxifying medicine and blood-activating and stasis-eliminating medicine accounting for the largest proportion(25/146 and 13/146,respectively).Conclusion This study analyzed and validated bioinformatics sequencing databases to elucidate the potential molecular mechanisms of DKD autophagy and predicted key diagnostic genes,potential therapeutic targets,and related Chinese medicines,laying a solid foundation for clinical research and application.展开更多
Approximately 30%-40%of individuals with diabetes develop chronic kidney disease during their lifetime,and patients with type 2 diabetes mellitus have a high risk of developing and progressing to this condition.The tw...Approximately 30%-40%of individuals with diabetes develop chronic kidney disease during their lifetime,and patients with type 2 diabetes mellitus have a high risk of developing and progressing to this condition.The two comorbidities represent a lethal combination that exacerbates both diseases.It is crucial to measure the glomerular filtration rate and to monitor and assess the renal functionality of these patients.Serum creatinine,the traditional marker of kidney assessment,has been shown to be susceptible to too many variables that can significantly alter the final estimated glomerular filtration rate outcome.Cystatin C-based formulas appear to have reasonable accuracy in this population and help to ensure better tailored therapy and renal assessment.The purpose of this editorial was to provide an examination of the advantage of using cystatin C as a valid marker for determining estimated glomerular filtration rate,free from any interfering factors,allowing a more accurate assessment of renal function.展开更多
Objective:To investigate the mechanisms underlying the renoprotective effects of celastrol,a bioactive compound extracted from the traditional Chinese medicinal plant Tripterygium wilfordii in diabetic kidney disease(...Objective:To investigate the mechanisms underlying the renoprotective effects of celastrol,a bioactive compound extracted from the traditional Chinese medicinal plant Tripterygium wilfordii in diabetic kidney disease(DKD).Methods:We established a DKD model using db/db mice and investigated the protective mechanisms of celastrol against DKD progression using integrated analysis of 16S rRNA sequencing and transcriptome analysis.We evaluated colon tissue damage using hematoxylin and eosin and immunofluorescence staining.In addition,16S rRNA sequencing and transcriptomic analyses were performed to explore the potential mechanisms of celastrol.Immunofluorescence staining,Western blotting and real-time quantitative polymerase chain reaction analysis were performed to confirm the PPAR signaling pathway related proteins in kidney tissues.Results:Celastrol alleviated colon injury and increased the expression of mucosal barrier markers,particularly occludin and zonula occludens-1.The 16S rRNA gene sequencing analysis demonstrated that treatment with celastrol altered the diversity and abundance of the gut microbiota.Spearman’s correlation analysis further revealed significant associations among gut microbial,renal injury markers,and serum lipid profiles.A subsequent renal transcriptome analysis revealed that celastrol significantly modulated the renal transcriptional landscape,primarily by regulating genes associated with the PPAR signaling pathway and lipid metabolism.Further investigations demonstrated that celastrol significantly downregulated adipose differentiation-related protein expression and attenuated DKD progression by activating the PPAR pathway.Conclusions:This study demonstrates that celastrol alleviates both colonic and renal injuries by modulating the gut-kidney axis through PPAR-mediated lipid metabolism regulation,indicating its potential as a therapeutic approach for DKD management.展开更多
基金2024 Medical Science Research Project Plan of Hebei Province:Research on the Rehabilitation Effect of Combined Exercise Intervention Based on a Hospital-Community-Family Model for Elderly Patients with Chronic Diseases(Project No.:20240083)Youth Science and Technology Project of the Hebei Provincial Health Department:Research on the Standardization Level of Self-Management in Patients with Diabetic Foot and Related Factors Affecting Wound Healing(Project No.:20190002)。
文摘Objective:To explore the application effect of combined exercise intervention based on the hospital-community-family model on intrinsic capacity in elderly patients with diabetes mellitus complicated by chronic kidney disease.Methods:Using convenience sampling,100 elderly patients with diabetes mellitus complicated by chronic kidney disease who received treatment in the endocrinology department of a tertiary A-level hospital from May 2024 to May 2025 were selected as the study subjects.They were randomly divided into an experimental group(50 cases)and a control group(50 cases)using a random number table method.The control group received routine health education and telephone follow-up,while the experimental group,in addition to the control group’s interventions,underwent combined exercise intervention based on the hospital-community-family model.Remote medical guidance was utilized to monitor and study the application effect of exercise intervention on intrinsic capacity in elderly patients with diabetes mellitus complicated by chronic kidney disease.Fasting blood glucose,2-hour postprandial blood glucose,glomerular filtration rate,6-minute walk distance,and scores in five dimensions of intrinsic capacity(exercise,cognition,psychology,vitality,and sensation)were measured before the intervention,at 4 weeks of intervention,and at 12 weeks of intervention for both groups.Results:Before the exercise intervention,there were no statistically significant differences(p>0.05)between the two groups in terms of fasting blood glucose,2-hour postprandial blood glucose,glomerular filtration rate,6-minute walk distance,and scores across five dimensions of intrinsic capacity:mobility,cognition,psychology,vitality,and sensation.After 12 weeks of intervention,the experimental group demonstrated significantly higher scores than the control group in glomerular filtration rate,6-minute walk distance,and the dimensions of mobility,cognition,and vitality within intrinsic capacity,with all differences being statistically significant(p<0.05).Conversely,the experimental group showed significantly lower scores than the control group in fasting blood glucose,2-hour postprandial blood glucose,and the psychological dimension of intrinsic capacity,with these differences also being statistically significant(p<0.05).Conclusion:Continuous nursing care utilizing telemedicine based on a hospital-community-family model combined with exercise intervention can effectively enhance exercise tolerance and intrinsic capacity in elderly patients with diabetes mellitus complicated by chronic kidney disease,thereby improving their quality of life.The effectiveness of the intervention is positively correlated with the duration of the intervention.
基金supported by grants from the National Natural Science Foundation of China(82474093,81973536)Jiangsu Province“Blue and Green Project”(184080H10240)+2 种基金Graduate Research Innovation Program of Jiangsu(KYCX23_0871)the National Natural Science Foundation of the Youth Science Fund Project(81703775)Health Research Program of Wuxi Municipal Health Commission(Q202107).
文摘Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.
基金Supported by the National Natural Science Foundation of China,No.82270942.
文摘BACKGROUND Diabetic kidney disease(DKD)has become the leading cause of end-stage renal disease.The disease characteristics,morbidity,and renal function progression rate of patients with DKD are all related to sex.This suggests that sex hormones may play an important role in changing renal function in patients with diabetes.There have been only a few studies on the correlation between sex hormones and DKD,which have contradictory conclusions.AIM To investigate the relationship between circulating sex hormone levels and DKD in men and postmenopausal women with type 2 diabetes mellitus(T2DM).METHODS This retrospective cross-sectional study included 356 patients with T2DM.Pearson or Spearman rank correlation analyses assessed the relationships between sex hormone levels and renal function indices.By adjusting for age,body mass index,systolic blood pressure,diastolic blood pressure,duration of diabetes,use of sodium-glucose cotrasporter-2 inhibitor,use of glucagon-like peptide-1 receptor agonist,hypertension,use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor,diabetic retinopathy,diabetic peripheral vascular disease,triglyceride,uric acid,and hemoglobin A1c,multiple linear regression and logistic regression analyses were conducted to identify factors influencing the urinary albumin/creatinine ratio(UACR)and DKD.RESULTS In men,dehydroepiandrosterone sulfate levels were inversely associated with log-transformed UACR after adjustment for covariate factors[regression coefficient(β)=-0.691,95%confidence interval(CI):-1.241 to-0.141 for quartile 4 vs quartile 1;P=0.006 for trend].Elevated levels of estradiol were positively associated with DKD[odds ratio(OR)=3.097,95%CI:1.083-8.856 for quartile 4 vs quartile 1;P=0.041 for trend],and higher luteinizing hormone(LH)levels were similarly associated with DKD(OR=4.164,95%CI:1.30-13.330 for quartile 4 vs quartile 1;P=0.048 for trend).In postmenopausal women,LH levels were positively correlated with log-transformed UACR and DKD(β=1.039,95%CI:0.284-1.794 for quartile 4 vs quartile 1;P=0.006 for trend and OR=15.117,95%CI:2.191-104.326 for quartile 4 vs quartile 1;P=0.004 for trend).Follicle-stimulating hormone(FSH)levels were also positively associated with DKD(OR=9.588,95%CI:1.680-54.709 for quartile 4 vs quartile 1;P=0.014 for trend).CONCLUSION In men with T2DM,elevated levels of estradiol and LH levels were positively associated with increased risk of DKD.In postmenopausal women with T2DM,high FSH and LH levels were positively associated with increased risk of DKD.
文摘BACKGROUND The progression of diabetic kidney disease(DKD)affects the patient’s kidney glomeruli and tubules,whose normal functioning is essential for maintaining normal calcium(Ca)and phosphorus(P)metabolism in the body.The risk of developing osteoporosis(OP)in patients with DKD increases with the aggravation of the disease,including a higher risk of fractures,which not only affects the quality of life of patients but also increases the risk of death.AIM To analyze the risk factors for the development of OP in patients with DKD and their correlation with Ca-P metabolic indices,fibroblast growth factor 23(FGF23),and Klotho.METHODS One hundred and fifty-eight patients with DKD who were admitted into the Wuhu Second People’s Hospital from September 2019 to May 2021 were selected and divided into an OP group(n=103)and a normal bone mass group(n=55)according to their X-ray bone densitometry results.Baseline data and differences in Ca-P biochemical indices,FGF23,and Klotho were compared.The correlation of Ca-P metabolic indices with FGF23 and Klotho was discussed,and the related factors affecting OP in patients with DKD were examined by multivariate logistic regression analysis.RESULTS The OP group had a higher proportion of females,an older age,and a longer diabetes mellitus duration than the normal group(all P<0.05).Patients in the OP group exhibited significantly higher levels of intact parathyroid hormone(iPTH),blood P,Ca-P product(Ca×P),fractional excretion of phosphate(FeP),and FGF23,as well as lower estimated glomerular filtration rate,blood Ca,24-hour urinary phosphate excretion(24-hour UPE),and Klotho levels(all P<0.05).In the OP group,25-(OH)-D3,blood Ca,and 24-hour UPE were negatively correlated with FGF23 and positively correlated with Klotho.In contrast,iPTH,blood Ca,Ca×P,and FeP exhibited a positive correlation with FGF23 and an inverse association with Klotho(all P<0.05).Moreover,25-(OH)-D3,iPTH,blood Ca,FePO4,FGF23,Klotho,age,and female gender were key factors that affected the lumbar and left femoral neck bone mineral density.CONCLUSION The Ca-P metabolism metabolic indexes,FGF23,and Klotho in patients with DKD are closely related to the occurrence and development of OP.
文摘Objective Diabetic kidney disease is a serious complication of diabetes,which is the leading cause of end-stage renal disease worldwide.Approximately 40%of individuals with diabetes develop diabetic kidney disease.At present,the most important drugs for diabetic kidney disease include renin-angiotensin-aldosterone system inhibitors,angiotensin receptor blockers,sodium-glucose cotransporter-2 inhibitors,and newly approved aldosterone receptor antagonists.However,to date,there are still no effective drugs to prevent diabetic kidney disease from progressing to end-stage renal disease.Network pharmacology combined with bioinformatics and pharmacology provides a powerful tool for studying the mechanism of drug action.Traditional Chinese medicine has accumulated rich experience in the treatment of diabetic kidney disease,and its multi-target,multi-component,and multi-pathway characteristics provide new ideas for modern medicine.This article reviews the research progress of network pharmacology and drug therapy in diabetic kidney disease.
基金Supported by Ministerio de Ciencia e Innovación(Instituto de Salud Carlos III-Fondo de Investigación Sanitaria),No.PI07/0870 and No.PI10/576Ministerio de Sanidad y Política Social(Dirección General de Terapias Avanzadas y Trasplante),No.TRA-182+1 种基金Sociedad Espaola de Nefrología y ACINEFResearch activity by Navarro-González JF is supported by Programa de Intensificación de la Actividad Investigadora,ISCIII/Canarias
文摘Diabetes mellitus entails significant health problems worldwide.The pathogenesis of diabetes is multifactorial,resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events,with metabolic and hemodynamic alterations.In this context,inflammation has emerged as a key pathophysiology mechanism.New pathogenic pathways will provide targets for prevention or future treatments.This review will focus on the implications of inflammation in diabetes mellitus,with special attention to inflammatory cytokines.
基金Supported by Science and Technology Research Program of Jilin Provincial Department of Education,No.JJKH20231218KJProject of the Jilin Provincial Administration of Traditional Chinese Medicine,No.2024111.
文摘Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal stem cells(MSCs)have shown great promise in tissue regeneration for DKD treatment and have protective effects against DKD,including decreased blood glucose and urinary protein levels and improved renal function.MSCs can directly differ-entiate into kidney cells or act via paracrine mechanisms to reduce apoptosis in DKD by modulating signaling pathways.MSC-derived extracellular vesicles(MSC-EVs)mitigate apoptosis and DKD-related symptoms by transferring miRNAs to target cells or organs.However,studies on the regulatory mechanisms of MSCs and MSC-EVs in apoptosis in DKD are insufficient.This review compre-hensively examines the mechanisms of apoptosis in DKD and research progress regarding the roles of MSCs and MSC-EVs in the disease process.
文摘Diabetes mellitus is one of the most common causes of chronic kidney disease.Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure.The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments,such as the vascular system and glomeruli.Glomerular alterations include thickening of the glomerular basement membrane,loss of podocytes,and segmental mesangiolysis,which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules.Beyond lesions directly related to diabetes,awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing.These nondiabetic lesions include focal segmental glomerulosclerosis,IgA nephropathy,and other primary or secondary renal disorders.Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches.However,the relationship between diabetes and the kidney is bidirectional;thus,new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases.Here,we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course,differential diagnosis,and therapeutic opportunities offered by novel drugs.
文摘Background: Worldwide, diabetic nephropathy-DN is the leading cause of end-stage kidney disease-ESKD, DN is a common cause of renal failure with a reported frequency of 10% - 15% in type-2-diabetes-mellitus-T2DM patients, however there is a great discrepancy between countries. The aim of the pre-sent study is to evaluate the findings of kidney biopsies performed on diabetic patients. Materials and Methods: We studied native kidney histopathological findings in the period from January 2016 till end of December 2018 done for patients with T2DM with chronic kidney diseases-CKD. Results: A total of 82 DM-patients, 50 males (61%) and 32 females (39%) with age mean (95% CI) of 50.8 (47.1 - 55.2) years for all patients, ranged between 15 to 65 years. Histological findings showed that 57.3% of patients had DN. While focal-segmental-glomerulosclerosis-FSGS was present in 20.7%—primary in 8.6% and secondary in 12.1%. IgA represented 4.9%, while Lupus nephritis, Membranous and drug induced interstitial nephritis were each present in 3.7%. MCD was present in 2.4%. Lastly diffuse proliferative GN, ANCA associated glomerulonephritis, and hypertensive nephrosclerosis accounted for 1.2%. Conclusion: The prevalence of NDKD is remarkably frequent in DM patients who underwent kidney biopsy and FSGS was the most frequent diagnosis. To get a proper histopathological diagnosis, an adequate tissue biopsy is needed with an adequate number of glomeruli. There is a great need for more consideration to biopsy diabetic patients, as the finding of NDKD requires a different therapeutic approach. This, hopefully, will help to manage these patients better and therefore, ameliorate the progression to ESKD over time and therefore delay the need for RRT.
基金supported by the Guizhou Provincial Basic Research Program(Natural Science)(No.Qiankehe Foundation-ZK[2023]General 428)Guizhou Provincial Department of Education 2024 Natural Science Research Project(Youth Science and Technology Talent Growth Project)(No.Qiankejiao[2024]116)the Science and Technology Foundation of Guizhou Provincial Health Commission(No.gzwkj2022-008).
文摘Objective Immune infiltration and ferroptosis play pivotal roles in the progression of diabetic kidney disease(DKD).However,investigations of immune cell-related ferroptosis genes(ICRFGs)in the context of DKD are insufficient.This study aimed to identify ICRFGs relevant to DKD and screen related inhibitors.Methods In this study,two DKD datasets from the GEO database were utilized.We adopted the ESTIMATE algorithm to generate microenvironment scores.The CIBERSORT and WGCNA methods were employed to identify immune-related differentially expressed genes(DEGs).The common ICRFGs were derived through a Venn diagram.We employed random forest,LASSO,K-M survival,receiver operating characteristic(ROC)curve,clinical relevance,and Spearman correlation analyses to select hub ICRFGs further.Immunohistochemical experiments were also performed to validate the expression.Additionally,we utilized the Selleck database to obtain ferroptosis-related compounds and used USCF Chimera 1.14 to minimize energy,combined with molecular dynamics(MD)simulations to explore possible ferroptosis inhibitors.Results Immunohistochemical analysis revealed that arachidonate 5-lipoxygenase(ALOX5)was significantly highly expressed in the db/db group.Clinical correlation and K-M survival analyses confirmed ALOX5 as the most crucial ICRFG in DKD.Furthermore,ALOX5 was significantly enriched in the terms ECM-receptor interaction,regulation of chemokine production,and regulation of the inflammatory response.A positive correlation was observed between ALOX5 and M1 macrophages,γδT cells,and monocytes.Moreover,virtual screening and MD revealed NSC348884,salvianolic acid B,and deltarasin as potential ferroptosis inhibitors in combination with ALOX5.Conclusion We identified ALOX5 as a reliable and prospective diagnostic marker associated with immunity and ferroptosis in DKD patients.
基金Supported by the Changsha Science and Technology Major Project,No.kh2205035the Hunan Traditional Chinese Medicine Science and Technology Project,No.2021061the Natural Science Foundation of Hunan Province,No.2025JJ80080。
文摘BACKGROUND Injury to the glomerular filtration barrier causes diabetic kidney disease(DKD),and glomerular endothelial-mesenchymal transition damages the filtration barrier of glomerular endothelial cells.Shenfushu granules(SFSGs)can treat chronic renal failure;however,their role and mechanism in DKD remain unclear.AIM To investigate the role of SFSGs in delaying DKD progression and their underlying mechanism in a streptozotocin-induced DKD mouse model.METHODS The microalbumin content in the urine and the blood glucose,creatinine,and blood urea nitrogen levels in the serum were measured.The expression and distribution ofα-smooth muscle actin(α-SMA),heparan sulfate(HS)and cluster of differentiation(CD)31 were observed through immunofluorescence or immunohistochemistry.Western blotting was conducted to measure the expression of CD31,α-SMA,PIK3R1,protein kinase B(AKT),phospho-PIK3R1,phospho-AKT,and heparanase-1.Network pharmacology was conducted to screen and identify the core components and targets of SFSGs.Molecular docking and dynamic simulations were performed to evaluate the binding ability of the core components of SFSGs to their core targets.RESULTS Compared with those in the model group,the 24-hour microalbuminuria(188.2±20.1 and 140.4±24.7 vs 323.2±44.4),serum creatinine(79.4±2.6 and 68.7±6.0 vs 110.2±4.8),blood urea nitrogen(14.4±1.1 and 13.1±0.5 vs 19.5±1.1),and renal index(20.3±1.0 and 19.6±0.8 vs 25.3±1.7)were significantly lower in the SFSGs(2.08 and 4.16 g/kg/day extract)-treated DKD mice.SFSGs inhibited the down regulation of CD31 and the upregulation ofα-SMA in the glomerular endothelial cells of DKD mice.Additionally,SFSGs suppressed the decrease in glycocalyx thickness and the expression of its component HS.Network pharmacology revealed that PIK3R1 was the core target of SFSGs.SFSGs markedly downregulate the expression of phospho-PIK3R1,phospho-AKT,and heparanase-1.However,the PIK3R1 agonist abolished the regulatory effect of SFSGs on the expression of CD31,α-SMA,and heparanase-1.CONCLUSION Collectively,these results suggest that SFSGs can significantly delay DKD progression and inhibit injury to the glycocalyx and the endothelial-mesenchymal transition of glomerular endothelial cells.This mechanism is related to PIK3R1/AKT/heparanase-1 signaling pathway regulation.
基金Supported by Science and Technology Research Program of Chongqing Municipal Education Commission,No.KJQN202100538Talent Innovation Project in Life Sciences of Chongqing Normal University,No.CSSK2023-04.
文摘Diabetic kidney disease(DKD),a primary cause of end-stage renal disease,results from progressive tissue remodeling and loss of kidney function.While single-cell RNA sequencing has significantly accelerated our understanding of cellular diversity and dynamics in DKD,its lack of spatial resolution limits insights into tissue-specific dysregulation and the microenvironment.Spatial transcriptomics(ST)is an innovative technology that combines gene expression with spatial localization,offering a powerful approach to dissect the molecular mechanisms of DKD.This mini-review introduces how ST has transformed DKD research by enabling spatially resolved analysis of cell interactions and identifying localized molecular alterations in glomeruli and tubules.ST has revealed dynamic intercellular communication within the renal microenvironment,lesion-specific gene expression patterns,and immune infiltration profiles.For example,SlideseqV2 has highlighted disease-specific cellular neighborhoods and associated signaling networks.Furthermore,ST has pinpointed key genes implicated in disease progression,such as fibrosis-related proteins and transcription factors in tubular damage.By integration of ST with computational tools such as machine learning and network-based analysis can help uncover gene regulatory mechanisms and potential therapeutic targets.However,challenges remain in limited spatial resolution,high data complexity,and computational demands.Addressing these limitations is essential for advancing precision medicine in DKD.
基金National Natural Science Foundation of China:Basic Research on the Mechanism of Organ Immune Damage and the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine(No.32141005)。
文摘OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.
基金This work was supported by the grants from National Natural Science Foundation of China(No.82174334)2022 Postgraduate Innovation Research Projects in Hainan Province(No.Qhys2022-273).
文摘Objective:To investigate the effects of Alpiniae oxyphyllae Fructus(AOF)on renal lipid deposition in diabetic kidney disease(DKD)and elucidate its molecular mechanisms.Methods:The mechanism of AOF in treating DKD was explored by network pharmacological enrichment analysis,molecular docking,and molecular dynamics simulation.The effects of AOF on renal function and lipid deposition were assessed in a mouse model of DKD and high glucose-stressed HK-2 cells.Cell viability and lipid accumulation were detected by CCK8 and oil red O staining.The expressions of PPARαand fatty acid oxidation-related genes(ACOX1 and CPT1A)were detected by quantitative RT-PCR,Western blot,and immunofluorescence.Furthermore,PPARαknockdown was performed to examine the molecular mechanism of AOF in treating DKD.Results:Network pharmacological enrichment analysis,molecular docking,and molecular dynamics simulation showed that the active compounds in AOF targeted PPARαand thus transcriptionally regulated ACOX1 and CPT1A.AOF lowered blood glucose,improved dyslipidemia,and attenuated renal injury in DKD mice.AOF-containing serum accentuated high glucose-induced decrease in cell viability and ameliorated lipid accumulation.Additionally,it significantly upregulated the expression of PPARα,ACOX1,and CPT1A in both in vivo and in vitro experiments,which was reversed by PPARαknockdown.Conclusions:AOF may promote fatty acid oxidation via PPARαto ameliorate renal lipid deposition in DKD.
基金Supported by National Natural Science Foundation of China,No.82205025,No.82374355,and No.82174293.
文摘BACKGROUND Diabetic kidney disease(DKD)stands as the key contributor to chronic kidney disease worldwide.Clinical studies have shown that Kunkui Baoshen decoction(KKBS)effectively reduces proteinuria and enhances renal function in DKD patients.However,its precise molecular targets and therapeutic mechanisms remain to be thoroughly clarified.AIM To evaluate the nephroprotective efficacy of KKBS in DKD and explore the underlying mechanisms of action.METHODS Liquid chromatography-tandem mass spectrometry was utilized to analyze the chemical constituents of KKBS.Metabonomic and transcriptomic analyses were conducted to identify key targets and pathways associated with the therapeutic effects of KKBS on DKD.The nephroprotective effects of KKBS were assessed both in high glucose-induced human kidney-2 cells and in db/db mice.A variety of assays were performed,including Cell Counting Kit-8,Western blot,quantitative reverse transcription-polymerase chain reaction,immunofluorescence,coimmunoprecipitation,periodic acid-Schiff staining,Masson staining,hematoxylin and eosin staining,immunohistochemistry,and mitochondrial morphology analysis.RESULTS The glutathione metabolic pathway emerged as the most prominent metabolic pathway in the metabonomic analysis of KKBS.Transcriptomic and bioinformatic analyses revealed that nuclear receptor coactivator 4(NCOA4)was instrumental in regulating ferroptosis within renal tubules of mice with DKD.Both in vitro and in vivo experiments showed that KKBS ameliorated renal dysfunction,mitigated renal tissue damage,and repressed the expression of autophagy-dependent ferroptosis markers and inflammatory fibrosis.Mechanistically,KKBS enhanced the interaction between the homologous to E6-AP C-terminus and RCC1-like domaincontaining E3 ubiquitin protein ligase(HERC2)and NCOA4,leading to K48-related ubiquitination and subsequent degradation of NCOA4.This process inhibited autophagy-dependent ferroptosis,reduced the release of pro-fibrotic inflammatory factors,and ultimately exerted an anti-fibrotic effect in DKD.CONCLUSION KKBS confers nephroprotection in DKD by modulating HERC2/NCOA4-mediated autophagy-dependent ferroptosis,thereby alleviating renal fibrosis.
文摘One of the most prevalent long-term effects of diabetes is diabetic kidney disease(DKD),which is linked to problems with the metabolism of amino acids,fats,and carbohydrates.The fundamental pathogenic mechanisms of DKD cannot be adequately treated by current clinical medicines;they can only slow the illness’s progression to end-stage renal disease.We will concentrate on integrating human umbilical cord mesenchymal stem cell(hUC-MSC)-related mechanisms and potential applications into the therapy of DKD,as this work shows that hUCMSCs can be used to treat metabolic liver obesity associated with diabetes.Future studies on the connection between hUC-MSCs and related illnesses ought to be promoted.
基金Supported by Industrial Technological Initiation Scholarship of National Council for Scientific and Technological Development,CNPq,Brazil,No.0932204294929829 and No.7414780530977345the Scientific Initiation Scholarship Programme(PIBIC)of National Council for Scientific and Technological Development,CNPq,Brazil,No.5763023359532159,No.6472982965854452,and No.7340128440641417the CNPq Research Productivity Fellow,No.4357511882624145.
文摘The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney disease.However,novel therapies,particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide-1(GLP-1)receptor agonists,which were initially developed for hyperglycemia management,have transformed the treatment of obesity,heart failure,cardiovascular disease,and more recently,DKD.SGLT2 inhibitors have consistently and significantly reduced cardiovascular events,albuminuria,and glomerular filtration rate,highlighting their efficacy across diverse clinical presentations for patients with kidney impairment.Although fewer studies have specifically investigated GLP-1 receptor agonists in patients with kidney disease,existing evidence underscores their potential to slow renal disease progression,reduce albuminuria,and improve clinically relevant outcomes.However,further research is needed to better identify patients most likely to benefit from treatment.Together,these therapies represent valuable advancements for DKD,offering significant reductions in morbidity and mortality and shifting the management of the disease by becoming essential pillars for the treatment of these patients.
基金National Natural Science Foundation of China(82170747),and Shanghai Key Laboratory of Traditional Chinese Clinical Medicine(20DZ2272200).
文摘Objective To predict the autophagy-related pathogenesis and key diagnostic genes of diabetic kidney disease(DKD)through bioinformatics analysis,and to identify related Chinese medicines.Methods Data from sequencing microarrays GSE30528,GSE30529,and GSE1009 in the Gene Expression Omnibus(GEO)were employed.Differentially expressed genes(DEGs)with adjusted P<0.05 from GSE30528 and GSE30529 were identified.Combining these DEGs with the human autophagy gene database,Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses,and protein-protein interaction(PPI)network analysis were conducted on the obtained DKD autophagy-related genes.Subsequently,the least absolute shrinkage and selection operator(LASSO)regression and support vector machinerecursive feature elimination(SVM-RFE)algorithms were adopted to select autophagy-related genes.The diagnostic capability of these genes was assessed through analysis with the external validation set from microarray GSE1009,and relevant Chinese medicines were inversely predicted using the SymMap database.Results A total of 2014 DEGs were selected from GSE30528 and GSE30529,leading to the identification of 37 DKD autophagy-related genes.GO analysis indicated 681 biological mechanisms,including autophagy regulation and plasma membrane microdomain activity.KEGG enrichment analysis identified 112 related signaling pathways.PPI network analysis showed a marked enrichment of autophagy-related genes in DKD.Through LASSO regression and SVM-RFE,four core diagnostic genes for autophagy in DKD were identified:protein phosphatase 1 regulatory subunit 15A(PPP1R15A),hypoxia inducible factor 1 alpha subunit(HIF1α),deleted in liver cancer 1(DLC1),and ceroid lipofuscinosis neuronal 3(CLN3).The external validation set demonstrated high diagnostic efficiency for these genes.Finally,146 kinds of potential Chinese medicines were predicted using the SymMap database,with heatclearing and detoxifying medicine and blood-activating and stasis-eliminating medicine accounting for the largest proportion(25/146 and 13/146,respectively).Conclusion This study analyzed and validated bioinformatics sequencing databases to elucidate the potential molecular mechanisms of DKD autophagy and predicted key diagnostic genes,potential therapeutic targets,and related Chinese medicines,laying a solid foundation for clinical research and application.
文摘Approximately 30%-40%of individuals with diabetes develop chronic kidney disease during their lifetime,and patients with type 2 diabetes mellitus have a high risk of developing and progressing to this condition.The two comorbidities represent a lethal combination that exacerbates both diseases.It is crucial to measure the glomerular filtration rate and to monitor and assess the renal functionality of these patients.Serum creatinine,the traditional marker of kidney assessment,has been shown to be susceptible to too many variables that can significantly alter the final estimated glomerular filtration rate outcome.Cystatin C-based formulas appear to have reasonable accuracy in this population and help to ensure better tailored therapy and renal assessment.The purpose of this editorial was to provide an examination of the advantage of using cystatin C as a valid marker for determining estimated glomerular filtration rate,free from any interfering factors,allowing a more accurate assessment of renal function.
基金Hangzhou Municipal Health Commission Project(A20231278)Zhejiang Province Medical and Health Technology Plan Project(2024KY219)+1 种基金Zhejiang Traditional Medicine and Technology Program,China(2024ZR114)Peak Discipline Nephrology of Hangzhou(Integrated Traditional and Western Medicine,2025HZGF12).
文摘Objective:To investigate the mechanisms underlying the renoprotective effects of celastrol,a bioactive compound extracted from the traditional Chinese medicinal plant Tripterygium wilfordii in diabetic kidney disease(DKD).Methods:We established a DKD model using db/db mice and investigated the protective mechanisms of celastrol against DKD progression using integrated analysis of 16S rRNA sequencing and transcriptome analysis.We evaluated colon tissue damage using hematoxylin and eosin and immunofluorescence staining.In addition,16S rRNA sequencing and transcriptomic analyses were performed to explore the potential mechanisms of celastrol.Immunofluorescence staining,Western blotting and real-time quantitative polymerase chain reaction analysis were performed to confirm the PPAR signaling pathway related proteins in kidney tissues.Results:Celastrol alleviated colon injury and increased the expression of mucosal barrier markers,particularly occludin and zonula occludens-1.The 16S rRNA gene sequencing analysis demonstrated that treatment with celastrol altered the diversity and abundance of the gut microbiota.Spearman’s correlation analysis further revealed significant associations among gut microbial,renal injury markers,and serum lipid profiles.A subsequent renal transcriptome analysis revealed that celastrol significantly modulated the renal transcriptional landscape,primarily by regulating genes associated with the PPAR signaling pathway and lipid metabolism.Further investigations demonstrated that celastrol significantly downregulated adipose differentiation-related protein expression and attenuated DKD progression by activating the PPAR pathway.Conclusions:This study demonstrates that celastrol alleviates both colonic and renal injuries by modulating the gut-kidney axis through PPAR-mediated lipid metabolism regulation,indicating its potential as a therapeutic approach for DKD management.
