摘要
目的研究尼可地尔通过调控热休克蛋白-70(HSP-70)对大鼠造影剂相关急性肾损伤(CA-AKI)的影响,对尼可地尔通过调控HSP-70对大鼠CA-AKI的保护作用及分子机制进行探究。方法将SD大鼠随机分为对照组、CA-AKI组、尼可地尔组、VER-155008组、尼可地尔+VER-155008组。对照组、CA-AKI组建模前给予生理盐水灌胃,尼可地尔组给予5 mg/kg尼可地尔灌胃,VER-155008组给予10μmol/kg HSP-70抑制剂VER-155008腹腔注射,尼可地尔+VER-155008组给予5 mg/kg尼可地尔灌胃及10μmol/kg VER-155008腹腔注射,连续7 d。除对照组外,其余5组均在给药后进行CA-AKI建模。建模后12 h时,检测血肌酐(Scr)、血尿素氮(BUN)、中性粒细胞明胶酶相关脂质释放素(NGAL)、肾损伤分子-1(KIM-1),苏木素伊红染色观察肾脏病理改变并进行肾小管病理损伤评分,Masson染色观察肾脏纤维化并计算肾小管间质纤维化相对面积,检测肾脏中白细胞介素-1β(IL-1β)、白细胞介素-18(IL-18)、肿瘤坏死因子-α(TNF-α)、超氧化物歧化酶(SOD)试、谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)水平、细胞凋亡率及裂解型caspase-3、HSP-70表达水平。结果CA-AKI组的Scr、BUN、NGAL、KIM-1、肾小管病理损伤评分、肾小管间质纤维化相对面积、肾脏中IL-1β、IL-18、TNF-α、MDA水平及细胞凋亡率、裂解型caspase-3及HSP-70表达水平均高于对照组(t=22.362、24.654、19.513、13.871、28.886、17.407、15.458、11.349、13.991、14.004、25.796、27.500、7.542,P<0.05),SOD、GSH-Px水平低于对照组(t=8.167、8.931,P<0.05);尼可地尔组的Scr、BUN、NGAL、KIM-1、肾小管病理损伤评分、肾小管间质纤维化相对面积、肾脏中IL-1β、IL-18、TNF-α、MDA水平及细胞凋亡率、裂解型caspase-3表达水平均低于CA-AKI组(t=13.415、15.834、12.369、11.396、17.903、11.204、10.369、7.663、4.629、10.219、18.295、13.156,P<0.05),SOD、GSH-Px水平及HSP-70表达水平均高于CA-AKI组(t=6.489、6.890、12.257,P<0.05);尼可地尔+VER-155008组的Scr、BUN、NGAL、KIM-1、肾小管病理损伤评分、肾小管间质纤维化相对面积、肾脏中IL-1β、IL-18、TNF-α、MDA水平及细胞凋亡率、裂解型caspase-3表达水平均高于尼可地尔组(t=11.256、9.846、7.668、4.992、10.095、9.266、8.537、6.219、8.360、6.078、14.640、11.853,P<0.05),SOD、GSH-Px水平及HSP-70表达水平均低于尼可地尔组(t=6.078、4.661、5.588,P<0.05)。结论尼可地尔通过上调HSP-70表达减轻大鼠CA-AKI并抑制肾脏炎症反应、氧化应激、细胞凋亡。
Objective To investigate the effect of nicorandil on contrast-induced acute kidney injury(CA-AKI)in rats and its underlying mechanism involving heat shock protein-70(HSP-70).Methods Sprague-Dawley rats were randomly divided into five groups:control,CA-AKI,nicorandil,VER-155008(HSP-70 inhibitor),and nicorandil+VER-155008.The control and CA-AKI groups received saline by gavage before modeling.The nicorandil group received nicorandil(5 mg/kg,gavage),the VER-155008 group received VER-155008(10μmol/kg,intraperitoneal injection),and the combined group received both drugs.Treatments were administered for seven consecutive days,followed by CA-AKI induction in all groups except the control.Twelve hours post-modeling,renal function was assessed by serum creatinine(Scr),blood urea nitrogen(BUN),neutrophil gelatinase-associated lipocalin(NGAL),and kidney injury molecule-1(KIM-1).Renal histopathological injury and fibrosis were evaluated by hematoxylin-eosin and Masson staining,respectively.Levels of interleukin-1β(IL-1β),interleukin-18(IL-18),tumor necrosis factor-α(TNF-α),superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),malondialdehyde(MDA),apoptosis rate,cleaved caspase-3,and HSP-70 expression were measured.Results Compared with the control group,the CA-AKI group exhibited significantly elevated Scr,BUN,NGAL,KIM-1,histological injury score,fibrotic area,renal IL-1β,IL-18,TNF-α,MDA,apoptosis rate,cleaved caspase-3,and HSP-70 expression(t=22.362,24.654,19.513,13.871,28.886,17.407,15.458,11.349,13.991,14.004,25.796,27.500,7.542,P<0.05),while SOD and GSH-Px levels were decreased(t=8.167,8.931,P<0.05).Compared with the CA-AKI group,nicorandil treatment significantly reduced Scr,BUN,NGAL,KIM-1,histological injury score,fibrotic area,IL-1β,IL-18,TNF-α,MDA,apoptosis rate,and cleaved caspase-3(t=13.415,15.834,12.369,11.396,17.903,11.204,10.369,7.663,4.629,10.219,18.295,13.156,P<0.05),while increasing SOD,GSH-Px,and HSP-70 expression(t=6.489,6.890,12.257,P<0.05).Scr,BUN,NGAL,KIM-1,renal tubule pathological injury score,the relative area of renal tubulointerstitial fibrosis,IL-1 beta,IL-18,IL-1β,IL-18,TNF-α,MDA levels,apoptosis rate and cleaved caspase-3 expression levels in kidney of nicorandil+VER-155008 group were higher than those in nicorandil group(t=11.256,9.846,7.668,4.992,10.095,9.266,8.537,6.219,8.360,6.078,14.640,11.853,P<0.05),SOD,GSH-Px levels and HSP-70 expression levels were lower than those of nicorandil group(t=6.078,4.661,5.588,P<0.05).Conclusion Nicorandil alleviates contrast-induced acute kidney injury in rats by upregulating HSP-70 expression.This effect is associated with reduced renal inflammation,oxidative stress,and apoptosis.
作者
朱波
饶海微
宣睿
李青
詹碧鸣
ZHU Bo;RAO Hai-wei;XUAN Rui;LI Qing;ZHAN Bi-ming(Department of Cardiology,the Second Affiliated Hospital of Nanchang University,Nanchang 330000,Jiangxi,China;不详)
出处
《广东医学》
2025年第9期1293-1299,共7页
Guangdong Medical Journal
基金
江西自然科学基金(20232BAB216003)
江西省教育厅科学技术研究项目(170159)。
