Objective To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor(MR)and the development of tubulointerstitial nephritis(TIN),and to evaluate the impact of MR on dysl...Objective To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor(MR)and the development of tubulointerstitial nephritis(TIN),and to evaluate the impact of MR on dyslipidemia,particularly secondary hyperlipemia,in patients with diabetic kidney disease.Methods We conducted a two-sample Mendelian randomization study using genome-wide association study(GWAS)summary data.Genetic variants associated with MR levels were selected as exposures,with TIN and lipid profiles[including low-density lipoprotein cholesterol(LDL-C),triglyceride,and high-density lipoprotein cholesterol]as outcomes.A two-step Mendelian randomization approach was used to assess TIN as a mediator,employing inverse variance weighted regression as the primary analysis,supplemented by Mendelian randomization-Egger,weighted median,and sensitivity analyses.Results Cytoplasmic unactivated MR level exhibited a significant causal association with a decreased risk of TIN(OR=0.8598,95%CI[0.7775-0.9508],P<0.001).Although no significant causal relationship was identified between MR level and secondary hyperlipemia,a potential association of cytoplasmic unactivated MR level with lower LDL-C levels was observed(OR=0.9901,95%CI[0.9821-0.9983],P=0.018).Additionally,TIN exhibited causal links with secondary hyperlipemia(OR=1.0016,95%CI[1.0002-1.0029],P=0.020)and elevated LDL-C(OR=1.0111,95%CI[1.0024-1.0199],P=0.012),particularly LDL-C in European males(OR=1.0230,95%CI[1.0103-1.0358],P<0.001).Inverse Mendelian randomization analysis revealed causal relationships between TIN and genetically predicted triglyceride(OR=0.7027,95%CI[0.6189-0.7978],P<0.001),high-density lipoprotein cholesterol(OR=1.1247,95%CI[1.0019-1.2626],P=0.046),and LDL-C(OR=0.8423,95%CI[0.7220-0.9827],P=0.029).Notably,TIN mediated 16.7%of the causal association between MR and LDL-C levels.Conclusions MR plays a critical role in the development of TIN and lipid metabolism,highlighting the potential of MR-antagonists in reducing renal damage and lipid metabolism-associated complications.展开更多
We experienced the first case with autoimmune polyglandular syndrome type 3(anti-thyroid peroxidase ant ib ody-positive hypothyroidism and anti-glutamic acid decar boxylase antibody-positive diabetes) complicated by m...We experienced the first case with autoimmune polyglandular syndrome type 3(anti-thyroid peroxidase ant ib ody-positive hypothyroidism and anti-glutamic acid decar boxylase antibody-positive diabetes) complicated by miner alocorticoid-responsive hyponatremia of the elderly.This case is also a rare slowly progressive insulin-dependent diabetes mellitus(SPIDDM) case,for which the patient has been treated for many years with sulfonylurea or glinide.Our observation also demonstrated that glucose metabolism in autoimmune diabetes such as SPIDDM is influenced by appetite,thyroid function and glucocorticoid effect.展开更多
AIM To evaluate the effects of mineralocorticoid receptor(MR) antagonists on mortality and inflammatory responses after hemorrhagic shock(HS) in rats.METHODS One hundred and two male Sprague–Dawley rats were randomly...AIM To evaluate the effects of mineralocorticoid receptor(MR) antagonists on mortality and inflammatory responses after hemorrhagic shock(HS) in rats.METHODS One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone(EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha(TNF-α) concentrations, and arterial blood gas at 8 h afterHS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery. RESULTS The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups(P = 0.888).CONCLUSION Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.展开更多
BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting effects.We recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardi...BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting effects.We recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardiac MR by directly phosphorylating it,thereby repressing its transcriptional activity.MR antagonist(MRA)drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure.Non-steroidal MRAs,such as finerenone,may provide better cardio-protection against Aldo than classic,steroidal MRAs,like spironolactone and eplerenone.AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade.METHODS We used H9c2 cardiomyocytes,which endogenously express the MR and GRK5.RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone.Unlike eplerenone,finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity,thus displaying inverse agonism.GRK5 is necessary for finerenone’s inverse agonism,since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity.Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels.Finally,GRK5 is necessary for the antiapoptotic,anti-oxidative,and anti-fibrotic effects of both finerenone and eplerenone against Aldo,as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis,oxidative stress,and fibrosis.CONCLUSION Finerenone,but not eplerenone,induces GRK5-dependent cardiac MR inhibition,which underlies,at least in part,its higher potency and efficacy,compared to eplerenone,as an MRA in the heart.GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.展开更多
Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin ...Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001,no other pharmacological agent tested in the past two decades have shown any clinically meaningful result.Recently,the sodium-glucose cotransporter-2 inhibitor(SGLT-2i),canagliflozin,has shown a significant reduction in the composite of hard renal and cardiovascular(CV)endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of reninangiotensin system blocker use.Another SGLT-2i,dapagliflozin,has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease(CKD),regardless of T2DM status.Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM.However,the full results of this trial have not yet been published.While the use of older steroidal mineralocorticoid receptor antagonists(MRAs)such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes,a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM,with reasonably acceptable side effects.展开更多
The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related....The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related.They are localized in the cytosol and translocate into the nucleus after ligand binding.GCRs and MRs can be co-expressed within the same cell,and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation.In critical illness,the hypothalamic-pituitary-adrenal axis is activated,and as a consequence,serum cortisol concentrations are high.However,a number of patients exhibit relatively low cortisol levels for the degree of illness severity.Glucocorticoid(GC)actions are facilitated by GCR,whose dysfunction leads to GC tissue resistance.The MR is unique in this family in that it binds to both aldosterone and cortisol.Endogenous GCs play a critical role in controlling inflammatory responses in critical illness.Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes,type 1 and type 2.11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone.The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues.In this review,we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.展开更多
Vascular remodeling is a pathological condition with structural changes of blood vessels.Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling.An integrated mode...Vascular remodeling is a pathological condition with structural changes of blood vessels.Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling.An integrated model of these two hypotheses emphasizes the importance of immune cells such as monocytes/macrophages,T cells,and dendritic cells.These immune cells are at the center stage to orchestrate cellular proliferation,migration,and interactions of themselves and other vascular cells including endothelial cells(ECs),vascular smooth muscle cells(VSMCs),and fibroblasts.These changes on vascular wall lead to inflammation and oxidative stress that are largely responsible for vascular remodeling.Mineralocorticoid receptor(MR)is a classic nuclear receptor.MR agonist promotes inflammation and oxidative stress and therefore exacerbates vascular remodeling.Conversely,MR antagonists have the opposite effects.MR has direct roles on vascular cells through non-genomic or genomic actions to modulate inflammation and oxidative stress.Recent studies using genetic mouse models have revealed that MR in myeloid cells,VSMCs and ECs all contribute to vascular remodeling.In conclusion,data in the past years have demonstrated that MR is a critical control point in modulating vascular remodeling.Studies will continue to provide evidence with more detailed mechanisms to support this notion.展开更多
The pathophysiology of preeclampsia(PE)remains unclear.PE spiral artery remodeling dysfunction and PE offspring cardiovascular future development has been a worldwide concern.We collected placental and umbilical arter...The pathophysiology of preeclampsia(PE)remains unclear.PE spiral artery remodeling dysfunction and PE offspring cardiovascular future development has been a worldwide concern.We collected placental and umbilical artery samples from normotensive and PE pregnancies.Mineralocorticoid receptor(MR)and its alternative splicing variant(ASV)expression and their biological effects on PE were examined.An MR ASV was found to be highly expressed in all PE samples and slightly expressed in about half of the normotensive samples(umbilical artery,~57.58%;placenta,~36.84%).The MR ASV expression was positively associated with blood pressure in both groups.The MR ASV protein changed the aldosterone-induced expression pattern of MR target genes related to ion exchanges and cell signaling pathways.The MR ASV can also impair the proliferation,migration,and tube formation ability of endothelial cells.These findings indicate that MR ASV in PE placenta plays a pathogenic role in PE pathophysiology,especially in endothelial dysfunction,and the existence of the MR ASV in PE umbilical artery provides a new direction in the study of PE offspring with increased risk of cardiovascular diseases.展开更多
Obesity and type 2 diabetes mellitus commonly coexist with heart failure(HF)and may contribute to the pathogenesis of HF with preserved ejection fraction.With progression in management therapies for HF with preserved ...Obesity and type 2 diabetes mellitus commonly coexist with heart failure(HF)and may contribute to the pathogenesis of HF with preserved ejection fraction.With progression in management therapies for HF with preserved ejection fraction,the mechanism behind beneficial actions of finerenone and semaglutide remains enigmatic.For decades,the cardiorenal protective effects of aldosterone blockage in patients with chronic kidney disease have been of significant interest.But due to multiple side effects,these trials were likely to stop.展开更多
Diabetes mellitus is a major contributor to kidney failure,with diabetic nephro-pathy being a common microvascular complication.The increasing prevalence of diabetes and its complications suggests a rise in associated...Diabetes mellitus is a major contributor to kidney failure,with diabetic nephro-pathy being a common microvascular complication.The increasing prevalence of diabetes and its complications suggests a rise in associated morbidity and mortality.Recent studies highlight increased mortality related to diabetic kidney disease,with disparities across demographic and geographic groups.Novel pharmacological treatments,including sodium-glucose cotransporter 2 inhibitors,non-steroidal mineralocorticoid receptor antagonists,and glucagon-like peptide-1 agonists,offer promise in slowing disease progression and reducing renal mortality.However,the growing epidemics of obesity and diabetes necessitate prioritizing public health policies focused on primary and secondary prevention,along with comprehensive multidisciplinary care.展开更多
BACKGROUND Type 2 diabetes mellitus(T2DM),one of the most common chronic metabolic diseases,is also one of the most significant risk factors for cardiovascular disease(CVD)and chronic kidney disease(CKD).AIM To conduc...BACKGROUND Type 2 diabetes mellitus(T2DM),one of the most common chronic metabolic diseases,is also one of the most significant risk factors for cardiovascular disease(CVD)and chronic kidney disease(CKD).AIM To conduct a systematic review and network meta-analysis of cardiovascular(CV)and renal benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA),sodium-glucose cotransporter-2 inhibitors(SGLT2i),and nonsteroidal mineralocorticoid receptor antagonists(nsMRA)in T2DM patients.METHODS We searched four databases-PubMed,EMBASE,Cochrane Library,and Web of Science-for publications from inception to March 6,2025.Total 500 participants were enrolled and had an intervention period of at least one year(or 52 weeks).Eligible studies included adult patients with T2DM and interventions with a placebo or another GLP-1RA,SGLT2i,or nsMRA.Data were standardized using Stata 17.0 software.The quality of evidence was assessed using the CINeMA and GRADE approaches.RESULTS Total 14970 articles were retrieved,of which 25 high-quality studies were included for the systematic review and network meta-analysis,covering 189797 patients and three drug classes(14 drugs).Network meta-analysis revealed low heterogeneity,thus ensuring reliable results.Meta-regression analysis indicated that baseline factors,such as comorbidities and blood glucose levels,did not affect our results.Overall,all included drugs demonstrated significant CV and renal benefits compared with the placebo.nsMRA showed the best efficacy in reducing the incidence of major adverse CV events and myocardial infarction.SGLT2i were most effective in reducing all-cause mortality,CV mortality,and the incidence of renal outcomes.GLP-1RA showed the greatest benefits in reducing the incidence of stroke.SC-semaglutide had the most significant effect on reducing major adverse CV events,oral semaglutide was most effective in reducing all-cause mortality and CV mortality,empagliflozin had the strongest effect in reducing composite renal outcomes and renal replacement therapy,canagliflozin was most effective in slowing the progression of proteinuria,and dapagliflozin showed the most significant reduction in end-stage renal disease.CONCLUSION T2DM,as one of the most common chronic metabolic diseases,is also one of the most significant risk factors for CVD and CKD.GLP-1RA,SGLT2i,and nsMRAs have emerged as novel therapeutic agents to comprehensively manage T2DM-related CVD and CKD.We conducted a network meta-analysis to compare the efficacy and safety of GLP-1RAs,SGLT2i,and nsMRA in patients with T2DM.展开更多
文摘Objective To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor(MR)and the development of tubulointerstitial nephritis(TIN),and to evaluate the impact of MR on dyslipidemia,particularly secondary hyperlipemia,in patients with diabetic kidney disease.Methods We conducted a two-sample Mendelian randomization study using genome-wide association study(GWAS)summary data.Genetic variants associated with MR levels were selected as exposures,with TIN and lipid profiles[including low-density lipoprotein cholesterol(LDL-C),triglyceride,and high-density lipoprotein cholesterol]as outcomes.A two-step Mendelian randomization approach was used to assess TIN as a mediator,employing inverse variance weighted regression as the primary analysis,supplemented by Mendelian randomization-Egger,weighted median,and sensitivity analyses.Results Cytoplasmic unactivated MR level exhibited a significant causal association with a decreased risk of TIN(OR=0.8598,95%CI[0.7775-0.9508],P<0.001).Although no significant causal relationship was identified between MR level and secondary hyperlipemia,a potential association of cytoplasmic unactivated MR level with lower LDL-C levels was observed(OR=0.9901,95%CI[0.9821-0.9983],P=0.018).Additionally,TIN exhibited causal links with secondary hyperlipemia(OR=1.0016,95%CI[1.0002-1.0029],P=0.020)and elevated LDL-C(OR=1.0111,95%CI[1.0024-1.0199],P=0.012),particularly LDL-C in European males(OR=1.0230,95%CI[1.0103-1.0358],P<0.001).Inverse Mendelian randomization analysis revealed causal relationships between TIN and genetically predicted triglyceride(OR=0.7027,95%CI[0.6189-0.7978],P<0.001),high-density lipoprotein cholesterol(OR=1.1247,95%CI[1.0019-1.2626],P=0.046),and LDL-C(OR=0.8423,95%CI[0.7220-0.9827],P=0.029).Notably,TIN mediated 16.7%of the causal association between MR and LDL-C levels.Conclusions MR plays a critical role in the development of TIN and lipid metabolism,highlighting the potential of MR-antagonists in reducing renal damage and lipid metabolism-associated complications.
文摘We experienced the first case with autoimmune polyglandular syndrome type 3(anti-thyroid peroxidase ant ib ody-positive hypothyroidism and anti-glutamic acid decar boxylase antibody-positive diabetes) complicated by miner alocorticoid-responsive hyponatremia of the elderly.This case is also a rare slowly progressive insulin-dependent diabetes mellitus(SPIDDM) case,for which the patient has been treated for many years with sulfonylurea or glinide.Our observation also demonstrated that glucose metabolism in autoimmune diabetes such as SPIDDM is influenced by appetite,thyroid function and glucocorticoid effect.
文摘AIM To evaluate the effects of mineralocorticoid receptor(MR) antagonists on mortality and inflammatory responses after hemorrhagic shock(HS) in rats.METHODS One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone(EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha(TNF-α) concentrations, and arterial blood gas at 8 h afterHS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery. RESULTS The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups(P = 0.888).CONCLUSION Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.
文摘BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting effects.We recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardiac MR by directly phosphorylating it,thereby repressing its transcriptional activity.MR antagonist(MRA)drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure.Non-steroidal MRAs,such as finerenone,may provide better cardio-protection against Aldo than classic,steroidal MRAs,like spironolactone and eplerenone.AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade.METHODS We used H9c2 cardiomyocytes,which endogenously express the MR and GRK5.RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone.Unlike eplerenone,finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity,thus displaying inverse agonism.GRK5 is necessary for finerenone’s inverse agonism,since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity.Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels.Finally,GRK5 is necessary for the antiapoptotic,anti-oxidative,and anti-fibrotic effects of both finerenone and eplerenone against Aldo,as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis,oxidative stress,and fibrosis.CONCLUSION Finerenone,but not eplerenone,induces GRK5-dependent cardiac MR inhibition,which underlies,at least in part,its higher potency and efficacy,compared to eplerenone,as an MRA in the heart.GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.
文摘Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001,no other pharmacological agent tested in the past two decades have shown any clinically meaningful result.Recently,the sodium-glucose cotransporter-2 inhibitor(SGLT-2i),canagliflozin,has shown a significant reduction in the composite of hard renal and cardiovascular(CV)endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of reninangiotensin system blocker use.Another SGLT-2i,dapagliflozin,has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease(CKD),regardless of T2DM status.Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM.However,the full results of this trial have not yet been published.While the use of older steroidal mineralocorticoid receptor antagonists(MRAs)such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes,a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM,with reasonably acceptable side effects.
文摘The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related.They are localized in the cytosol and translocate into the nucleus after ligand binding.GCRs and MRs can be co-expressed within the same cell,and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation.In critical illness,the hypothalamic-pituitary-adrenal axis is activated,and as a consequence,serum cortisol concentrations are high.However,a number of patients exhibit relatively low cortisol levels for the degree of illness severity.Glucocorticoid(GC)actions are facilitated by GCR,whose dysfunction leads to GC tissue resistance.The MR is unique in this family in that it binds to both aldosterone and cortisol.Endogenous GCs play a critical role in controlling inflammatory responses in critical illness.Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes,type 1 and type 2.11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone.The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues.In this review,we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.
基金supported by grants from the One Hundred Talents Program of the Chinese Academy of Sciences(2012OHTP06)the National Basic Research Program of China(2012CB524900)the National Natural Science Foundation of China(91339110,31371153,31171133)
文摘Vascular remodeling is a pathological condition with structural changes of blood vessels.Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling.An integrated model of these two hypotheses emphasizes the importance of immune cells such as monocytes/macrophages,T cells,and dendritic cells.These immune cells are at the center stage to orchestrate cellular proliferation,migration,and interactions of themselves and other vascular cells including endothelial cells(ECs),vascular smooth muscle cells(VSMCs),and fibroblasts.These changes on vascular wall lead to inflammation and oxidative stress that are largely responsible for vascular remodeling.Mineralocorticoid receptor(MR)is a classic nuclear receptor.MR agonist promotes inflammation and oxidative stress and therefore exacerbates vascular remodeling.Conversely,MR antagonists have the opposite effects.MR has direct roles on vascular cells through non-genomic or genomic actions to modulate inflammation and oxidative stress.Recent studies using genetic mouse models have revealed that MR in myeloid cells,VSMCs and ECs all contribute to vascular remodeling.In conclusion,data in the past years have demonstrated that MR is a critical control point in modulating vascular remodeling.Studies will continue to provide evidence with more detailed mechanisms to support this notion.
基金This work was supported by the National Key Research and Development Program of China(2017YFC1001303)International Cooperation Project of China and Canada NSFC(81661128010)+1 种基金National Natural Science Foundation of China(31471405,81671456,and 81671412)the National Key Basic Research Program(2013CB967404).
文摘The pathophysiology of preeclampsia(PE)remains unclear.PE spiral artery remodeling dysfunction and PE offspring cardiovascular future development has been a worldwide concern.We collected placental and umbilical artery samples from normotensive and PE pregnancies.Mineralocorticoid receptor(MR)and its alternative splicing variant(ASV)expression and their biological effects on PE were examined.An MR ASV was found to be highly expressed in all PE samples and slightly expressed in about half of the normotensive samples(umbilical artery,~57.58%;placenta,~36.84%).The MR ASV expression was positively associated with blood pressure in both groups.The MR ASV protein changed the aldosterone-induced expression pattern of MR target genes related to ion exchanges and cell signaling pathways.The MR ASV can also impair the proliferation,migration,and tube formation ability of endothelial cells.These findings indicate that MR ASV in PE placenta plays a pathogenic role in PE pathophysiology,especially in endothelial dysfunction,and the existence of the MR ASV in PE umbilical artery provides a new direction in the study of PE offspring with increased risk of cardiovascular diseases.
文摘Obesity and type 2 diabetes mellitus commonly coexist with heart failure(HF)and may contribute to the pathogenesis of HF with preserved ejection fraction.With progression in management therapies for HF with preserved ejection fraction,the mechanism behind beneficial actions of finerenone and semaglutide remains enigmatic.For decades,the cardiorenal protective effects of aldosterone blockage in patients with chronic kidney disease have been of significant interest.But due to multiple side effects,these trials were likely to stop.
文摘Diabetes mellitus is a major contributor to kidney failure,with diabetic nephro-pathy being a common microvascular complication.The increasing prevalence of diabetes and its complications suggests a rise in associated morbidity and mortality.Recent studies highlight increased mortality related to diabetic kidney disease,with disparities across demographic and geographic groups.Novel pharmacological treatments,including sodium-glucose cotransporter 2 inhibitors,non-steroidal mineralocorticoid receptor antagonists,and glucagon-like peptide-1 agonists,offer promise in slowing disease progression and reducing renal mortality.However,the growing epidemics of obesity and diabetes necessitate prioritizing public health policies focused on primary and secondary prevention,along with comprehensive multidisciplinary care.
基金Supported by National Natural Science Foundation of China,No.82305205Young Elite Scientists Sponsorship Program by CACM,No.CACM-2023-QNRC2-A05+1 种基金the Safeguard Project of Guang'anmen Hospital,China Academy of Chinese Medical Sciences,No.GAMHH9324001the Special Fund for Outstanding Young Scientific Talent Training of the Fundamental Research Business Expenses of the China Academy of Chinese Medical Sciences,No.ZZ18-YQ-011.
文摘BACKGROUND Type 2 diabetes mellitus(T2DM),one of the most common chronic metabolic diseases,is also one of the most significant risk factors for cardiovascular disease(CVD)and chronic kidney disease(CKD).AIM To conduct a systematic review and network meta-analysis of cardiovascular(CV)and renal benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA),sodium-glucose cotransporter-2 inhibitors(SGLT2i),and nonsteroidal mineralocorticoid receptor antagonists(nsMRA)in T2DM patients.METHODS We searched four databases-PubMed,EMBASE,Cochrane Library,and Web of Science-for publications from inception to March 6,2025.Total 500 participants were enrolled and had an intervention period of at least one year(or 52 weeks).Eligible studies included adult patients with T2DM and interventions with a placebo or another GLP-1RA,SGLT2i,or nsMRA.Data were standardized using Stata 17.0 software.The quality of evidence was assessed using the CINeMA and GRADE approaches.RESULTS Total 14970 articles were retrieved,of which 25 high-quality studies were included for the systematic review and network meta-analysis,covering 189797 patients and three drug classes(14 drugs).Network meta-analysis revealed low heterogeneity,thus ensuring reliable results.Meta-regression analysis indicated that baseline factors,such as comorbidities and blood glucose levels,did not affect our results.Overall,all included drugs demonstrated significant CV and renal benefits compared with the placebo.nsMRA showed the best efficacy in reducing the incidence of major adverse CV events and myocardial infarction.SGLT2i were most effective in reducing all-cause mortality,CV mortality,and the incidence of renal outcomes.GLP-1RA showed the greatest benefits in reducing the incidence of stroke.SC-semaglutide had the most significant effect on reducing major adverse CV events,oral semaglutide was most effective in reducing all-cause mortality and CV mortality,empagliflozin had the strongest effect in reducing composite renal outcomes and renal replacement therapy,canagliflozin was most effective in slowing the progression of proteinuria,and dapagliflozin showed the most significant reduction in end-stage renal disease.CONCLUSION T2DM,as one of the most common chronic metabolic diseases,is also one of the most significant risk factors for CVD and CKD.GLP-1RA,SGLT2i,and nsMRAs have emerged as novel therapeutic agents to comprehensively manage T2DM-related CVD and CKD.We conducted a network meta-analysis to compare the efficacy and safety of GLP-1RAs,SGLT2i,and nsMRA in patients with T2DM.
