艾塞那肽对糖尿病大鼠肾脏损伤的保护作用

目的：探讨GLP-1类似物艾塞那肽（exenatide）对链脲佐菌素诱导的糖尿病大鼠肾脏的保护作用。方法：SD大鼠随机分为正常组（NC组,n=8）和模型组;模型组给予高脂高糖饲料,喂养4周后腹腔注射STZ（30 mg·kg^-1）建模,72 h后以血糖≥ 16.7 mmol·L^-1为糖尿病成模标准,将成模大鼠随机分为糖尿病对照组（DM组,n=10）、3 μg·kg^-1艾塞那肽干预（Ex-1）组和6μg·kg^-1艾塞那肽干预（Ex-2）组;艾塞那肽组连续皮下注射艾塞那肽（bid）12周,NC组和DM组注射等容积溶剂;测定各组大鼠糖脂代谢变化和肾功能指标如血肌酐（Scr）、尿肌酐（Ucr）、尿素氮（BUN）、24 h尿微量白蛋白排出率（24 h UMA）并计算肌酐清除率（Ccr）;测定肾组织氧化应激指标超氧化物歧化酶（SOD）、丙二醛（MDA）和谷胱甘肽过氧化物酶（GSH-Px）;HE染色观察肾组织病理形态及ELISA法测定肾组织糖基化终末产物AGEs水平。结果：与糖尿病组相比,艾塞那肽可明显改善糖尿病大鼠糖脂代谢,血糖、糖基化血红蛋白（HbAlc）、甘油三脂及胆固醇值均下降（P < 0.05）,肾功能指标明显好转（P < 0.05）且肌酐清除率下降（P < 0.05）,提示肾小球高滤过状态;同时改善糖尿病引起的肾组织病理结构改变,AGEs浓度下降（P < 0.05）,氧化应激指标SOD和GSH-Px活力升高,MDA含量降低（P < 0.05）。结论：艾塞那肽具有肾脏保护作用,其机制可能与抑制糖尿病大鼠肾组织的AGEs生成和改善氧化应激有关。     

前列地尔联合益肾化湿颗粒对糖尿病肾病患者血糖、血脂、肾功能以及尿足细胞相关蛋白的影响

目的:分析前列地尔联合益肾化湿颗粒对糖尿病肾病患者血糖、血脂、肾功能以及尿足细胞相关蛋白的影响。方法:98例糖尿病肾病患者按抽签法分为对照组与实验组,各49例,对照组予以前列地尔治疗,实验组基于对照组加用益肾化湿颗粒治疗,比较两组疗效,糖化血红蛋白(Hb A1c)、血糖(FPG)、餐后2 h血糖低(2h PG),甘油三脂(TG)、总胆固醇(TC)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C),血尿素氮(BUN)、肌酐(Cr)、β2微球蛋白(β2-MG)、胱抑素(Cys-C),尿足细胞标志蛋白(PCX)nephrin,安全性。结果:实验组总有效率高于对照组(P0.05)。治疗后,两组Hb Alc、FPG、2h PG比较无差异(P0.05)。实验组TG、TC、LDL-C、BUN、Cr、β2-MG、Cys-c、PCX、尿nephrin/尿Cr低于对照组(P0.05)。实验组HDL-C高于对照组(P0.05)。结论:前列地尔联合益肾化湿颗粒治疗对糖尿病肾病的疗效确切,可利于血糖、血脂、肾功能的改善,降低尿足细胞相关蛋白的浓度。     

他克莫司联合黄葵胶囊治疗难治性膜性肾病的临床疗效

目的:探讨他克莫司联合黄葵胶囊治疗难治性膜性肾病疗效及安全性。方法:选取2014年3月-2015年10月我院收治的60例难治性膜性肾病患者,按随机数字表法分为观察组和对照组各30例,对照组给予泼尼松治疗,观察组在此基础上增加他克莫司联合黄葵胶囊口服,两组均治疗6个月,观察两组临床疗效,检测并对比两组治疗前后尿蛋白(uPRO)、血清白蛋白(sALB)、血清肌酐(sCr)、血谷丙转氨酶(sALT)、肿瘤坏死因子α(TNF-α)、转化生长因子β1(TGF-β1)以及不良反应情况。结果:观察组的有效率高于对照组(P0.05);治疗后两组uPRO、TNF-α、TGF-β1均明显降低,sALB、sCr明显升高(P0.05),且观察组uPRO、TNF-α、TGF-β1低于对照组(P0.05);两组不良反应发生率比较差异无统计学意义(P0.05)。结论:他克莫司联合黄葵胶囊治疗难治性膜性肾病具有较好的疗效,降低肾功能损伤,不良反应低,值得临床推广。     

血清Hcy与CysC 对早期2型糖尿病肾病的临床诊断价值分析

目的:分析血清同型半胱氨酸(Hcy)与胱抑素C(CysC)对早期2型糖尿病肾病的临床诊断价值。方法:选择2013年5月至2016年5月我院收治的早期糖尿病肾病患者60例为A组,选取同期我院收治的单纯糖尿病患者60例为B组,另选我院同期健康体检者60例为C组,检测三组的血清Hcy、CysC、血尿素氮(BUN)、血肌酐(Scr)、尿蛋白排泄率(UAER)。结果:与C组比较,A组和B组的BUN、Scr、UAER均升高(P0.05),A组的UAER高于B组(P0.05),但A组的BUN、Scr与B组比较,组间差异无统计学意义(P 0.05)。A组的病程明显高于B组(P0.05)。与C组比较,A组Hcy与CysC水平升高(P0.05),B组的Hcy水平升高(P0.05),CysC水平升高,但差异无统计学意义(P 0.05);与B组比较,A组Hcy与CysC水平升高(P0.05)。A组的Hcy、CysC、Hcy+CysC阳性率均明显高于B组和C组(P0.05),B组Hcy、CysC、Hcy+CysC阳性率均明显高于C组(P0.05);A组和B组的Hcy+CysC联合检测的阳性率高于Hcy、CysC的单独检测阳性率(P0.05)。Hcy与病程、BUN、Scr、UAER均呈正相关,相关系数r=0.650、0.488、0.596、0.761,P0.05,CysC与病程、BUN、Scr、UAER均呈正相关,相关系数r=0.681、0.502、0.601、0.825,P0.05。结论:血清Hcy与CysC可及时、准确的反应2型糖尿病患者的肾损伤情况,从而有利于早期2型糖尿病肾病的及时检出。     

Plasmin reduces fibronectin deposition by mesangial cells in a protease-activated receptor-1 independent manner

BackgroundProtease-activated receptor-1 (PAR-1) potentiates diabetic nephropathy (DN) as evident from reduced kidney injury in diabetic PAR-1 deficient mice. Although thrombin is the prototypical PAR-1 agonist, anticoagulant treatment does not limit DN in experimental animal models suggesting that thrombin is not the endogenous PAR-1 agonist driving DN.ObjectivesTo identify the endogenous PAR-1 agonist potentiating diabetes-induced nephropathy.MethodsUnbiased protease expression profiling in glomeruli from human kidneys with DN was performed using publically available microarray data. The identified prime candidate PAR-1 agonist was subsequently analysed for PAR-1-dependent induction of fibrosis in vitro.ResultsOf the 553 proteases expressed in the human genome, 247 qualified as potential PAR-1 agonists of which 71 were significantly expressed above background in diabetic glomeruli. The recently identified PAR-1 agonist plasmin(ogen), together with its physiological activator tissue plasminogen activator, were among the highest expressed proteases. Plasmin did however not induce mesangial proliferation and/or fibronectin deposition in vitro. In a PAR-1 independent manner, plasmin even reduced fibronectin deposition.ConclusionExpression profiling identified plasmin as potential endogenous PAR-1 agonist driving DN. Instead of inducing fibronectin expression, plasmin however reduced mesangial fibronectin deposition in vitro. Therefore we conclude that plasmin may not be the endogenous PAR-1 agonist potentiating DN.     

BMP Signaling and Podocyte Markers Are Decreased in Human Diabetic Nephropathy in Association With CTGF Overexpression

Diabetic nephropathy is characterized by decreased expression of bone morphogenetic protein-7 (BMP-7) and decreased podocyte number and differentiation. Extracellular antagonists such as connective tissue growth factor (CTGF; CCN-2) and sclerostin domain-containing-1 (SOSTDC1; USAG-1) are important determinants of BMP signaling activity in glomeruli. We studied BMP signaling activity in glomeruli from diabetic patients and non-diabetic individuals and from control and diabetic CTGF^+/+ and CTGF^+/− mice. BMP signaling activity was visualized by phosphorylated Smad1, -5, and -8 (pSmad1/5/8) immunostaining, and related to expression of CTGF, SOSTDC1, and the podocyte differentiation markers WT1, synaptopodin, and nephrin. In control and diabetic glomeruli, pSmad1/5/8 was mainly localized in podocytes, but both number of positive cells and staining intensity were decreased in diabetes. Nephrin and synaptopodin were decreased in diabetic glomeruli. Decrease of pSmad1/5/8 was only partially explained by decrease in podocyte number. SOSTDC1 and CTGF were expressed exclusively in podocytes. In diabetic glomeruli, SOSTDC1 decreased in parallel with podocyte number, whereas CTGF was strongly increased. In diabetic CTGF^+/− mice, pSmad1/5/8 was preserved, compared with diabetic CTGF^+/+ mice. In conclusion, in human diabetic nephropathy, BMP signaling activity is diminished, together with reduction of podocyte markers. This might relate to concomitant overexpression of CTGF but not SOSTDC1. (J Histochem Cytochem 57:623–631, 2009)     

MicroRNA-21 protects from mesangial cell proliferation induced by diabetic nephropathy in db/db mice

Diabetic nephropathy (DN) is a major diabetic complication. But the initiating molecular events triggering DN are unknown. Recent researches have addressed the role of microRNAs in diabetes and its complications. In this study, we looked for microRNAs expression during early DN, and showed microRNA-21 (miR-21) expression was downregulated in response to early DN in vitro and in vivo. Over-expression of miR-21 inhibited proliferation of mesangial cells and decreased the 24-h urine albumin excretion rate in diabetic db/db mice. Moreover, we identified PTEN as a target of miR-21. We also found PI3 K and p-Akt increased in miR-21 treated mesangial cells and db/db mice. Overall, these studies for the first time provide evidence for the potential role of miR-21 in early DN.