Rosiglitazone protects diabetic rats against kidney injury through the suppression of renal matrix metalloproteinase-9 expression

In this study, the effects of rosiglitazone on renal matrix metalloproteinase-9 (MMP-9) expression and its possible renoprotective mechanisms were investigated in streptozotocin-induced diabetic rats. We examined the urinary excretion rates of albumin (ALB), retinal-binding protein (RBP) and MMP-9 in control healthy rats (group C, n = 8), untreated diabetic rats (group D, n = 8) and diabetic rats treated with rosiglitazone (5mg/kg/day) (group R, n = 8) at eighth week. The renal tissue of diabetic rats was obtained for observing renal pathological changes by electron microscope and examining the expression of renal MMP-9 mRNA by RT-PCR. Our results showed that urinary excretion rates of MMP-9. ALB and RBP were significantly increased concurrently with the expression of renal MMP-9mRNA in group D compared with those of group C. Rosiglitazone significantly reduced urinary excretion rates of ALB, RBP and MMP-9 as well as the expression of renal MMP-9 mRNA. In addition, urinary excretion rate of MMP-9 showed positive relationship with urinary excretion rates of ALB and RBP. In conclusion, rosiglitazone definitely protects diabetic rats against renal injury, which may be partly associated with decreasing expression of renal MMP-9 mRNA and urinary MMP-9 production.     

Urinary MCP-1 and RBP: Independent predictors of renal outcome in macroalbuminuric diabetic nephropathy

BackgroundAlbuminuria has been considered a sine qua non condition for the diagnosis of diabetic nephropathy (DN) and has been widely used as a surrogate outcome of chronic kidney disease (CKD). However, recent data suggest that albuminuria may fail as a biomarker in a subset of patients, and the search for novel markers is intense.MethodsWe analyzed the role of urinary RBP and of serum and urinary cytokines (TGF-beta, MCP-1 and VEGF) as predictors of the risk of dialysis, doubling of serum creatinine or death (primary outcome, PO) in 56 type 2 diabetic patients with macroalbuminuric DN.ResultsMean follow-up time was 30.7 ± 10 months. Urinary RBP and MCP-1 were significantly higher in patients presenting the PO, whereas no difference was shown for TGF-β or VEGF. In the Cox regression, urinary RBP, MCP-1 and VEGF were positively associated and serum VEGF was inversely related to the risk of the PO. However, after adjustments for creatinine clearance, proteinuria, and blood pressure only urinary RBP (OR 11.6; 95% CI 2.7–49.2, p = 0.001 for log RBP) and urinary MCP-1 (OR 11.0; 95% CI 1.6–76.4, p = 0.02 for log MCP-1) remained as significant independent predictors of the PO.ConclusionUrinary RBP and MCP-1 are independently related to the risk of CKD progression in patients with macroalbuminuric DN. Whether these biomarkers have a role in the setting of normoalbuminuria and microalbuminuria in DN should be further investigated.     

辛伐他汀对糖尿病大鼠肾脏保护作用及对尿VEGF排泄的影响

目的观察辛伐他汀对糖尿病大鼠肾脏保护作用及对尿中血管内皮生长因子（VEGF）排泄的影响。方法Wistar大鼠24只,分为正常对照（NC）组、糖尿病（DM）组、辛伐他汀组（Sim）组。于成模后第2、4、8周时,检测各组的血糖、12小时尿视黄醇结合蛋白（RBP）、白蛋白（Alb）、VEGF排泄率,第8周时用透视电镜检查肾小球基底膜、系膜区的病理改变。结果（1）第2、4、8周时,DM组和Sim组尿Alb、RBP、VEGF排泄率均高于NC组（P〈0.01）,Sim组较DM组明显减少（P〈0.01）;尿VEGF排泄率与尿Alb、RBP排泄率及肾脏肥大指数存在正相关关系。（2）光镜和电镜下Sim组肾小球和肾小管-肾间质病变较DM组明显减轻,同NC组相比仅有少量病变。结论辛伐他汀对糖尿病大鼠肾脏具有保护作用,可能与其抑制肾脏VEGF过度表达有关。     

Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy

Monocyte chemoattractant protein-1 (MCP-1), is a chemokine that mediates renal interstitial inflammation, tubular atrophy, and interstitial fibrosis by recruiting monocytes/macrophages into renal tubulointerstitium. Recent studies have demonstrated that protein overload in renal tubular cells up-regulates MCP-1 gene and its protein expression. Therefore, we hypothesized that increased expression of MCP-1 in renal tubuli, probably triggered by an increase in the leakage of plasma protein from glomerular capillary to tubular fluid, may contribute to renal tubular damage and accelerate the progression of diabetic nephropathy. To test this hypothesis, we examined urinary excretion levels of MCP-1 and N-acetylglucosaminidase (NAG), a sensitive marker of renal tubular damage, in Japanese Type II diabetic patients with normoalbuminuria (n=29), microalbuminuria (n=25), and macroalbuminuria (n=18). The median urinary excretion level of MCP-1 in patients with macroalbuminuria (394.4 ng/g creatinine) was significantly elevated compared to the levels in patients with normoalbuminuria and microalbuminuria (159.6 and 193.9 ng/g creatinine, respectively). Furthermore, the urinary MCP-1 excretion level was positively correlated with urinary excretion levels of albumin (r=.816, P<.001) and NAG (r=.569, P<.001) in all subjects. These results suggest that MCP-1 is produced in renal tubular cells and released into urine in proportion to the degree of proteinuria (albuminuria), and that increased MCP-1 expression in renal tubuli contributes to renal tubular damage. Therefore, we conclude that heavy proteinuria itself may accelerate the progression of diabetic nephropathy by increasing the MCP-1 expression in renal tubuli.     

依那普利对糖尿病大鼠肾脏保护作用的实验研究

目的 研究依那普利对糖尿病大鼠肾脏的保护作用。方法 应用依那普利对糖尿病大鼠进行了１０周治疗,观察了其对糖尿病大鼠肾脏的保护作用。结果 对照组糖尿病大鼠肾小球滤过度,肾血流量,滤过分数及尿白蛋白均较正常对照组明显升高,肾小球基底膜不规则增厚,突触融合。依那普利治疗后糖尿病大鼠ＧＦＲ,ＲＰＦ,ＦＦ及ＵＡ均较糖尿病对照组明显降低,病理学异常不明显。     

伊贝沙坦对大鼠糖尿病模型肾脏肥大和肾小球毛细血管基底膜厚度的影响

目的 观察伊贝沙坦对大鼠糖尿病模型肾脏肥大和肾小球毛细血管基底膜厚度的影响。方法 将SD大鼠分为糖尿病肾病组(A组)、伊贝沙坦治疗组(B组)、健康对照组(C组),A和B组大鼠制成糖尿病模型,B组予以50mg／kg伊贝沙坦灌胃。观察第4、8、12周大鼠的血糖、体重、尿白蛋白、24h尿蛋白的改变及第12周时的肌酐清除率(Ccr)、肾重、肾脏肥大指数、肾组织总蛋白含量、肾小球面积和体积、肾小球毛细血管基底膜(GBM)厚度的改变。通过免疫组化观察肾结缔组织生长因子(CTGF)和转化生长因子(TGF)-βl的表达。结果 A组和B组大鼠血糖较C组明显升高且维持在一个较高水平(P＜0．01)。A组大鼠的体重较C组明显下降,B组有所增加(P＜0．05)。随时间的推移(第4、8、12周),A组大鼠尿蛋白、尿白蛋白逐渐增加,B组明显减少(P＜0．01)。A组大鼠Ccr较C组显著升高(P＜0．01),B组Ccr明显下降(P＜0．05)。至第12周时,A组大鼠肾脏重量、肾脏肥大指数、肾组织总蛋白含量、肾小球面积和体积均较C组明显增加(P＜0．01),B组均较A组降低(P＜0．01,P＜0．05)。免疫组化半定量分析显示,A组大鼠CTGF与TGF-βl的表达均高于C组(P＜0．01),B组明显低于A组(P＜0．01,P＜0．05)。A组大鼠GBM较C组明显增厚(P＜0．01),B组较A组明显变薄(P＜0．01）。肾小球CTGF、TGF—βl的表达与肾脏体积呈正相关(r＝0．83,r＝0．83;P＜0．05)。结论 早期应用伊贝沙坦可抑制糖尿病大鼠早期肾脏肥大和CTGF表达等。     

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.     

罗格列酮对糖尿病大鼠肾脏色素上皮衍生因子、基质金属蛋白酶2及转化生长因子β1表达的影响

45只SD大鼠分为正常对照组、糖尿病对照组、糖尿病罗格列酮治疗组,实验12周末以免疫组织化学和RT-PCR检测肾脏色素上皮衍生因子(PEDF)、基质金属蛋白酶2(MMP-2)和转化生长因子β1(TGF-β1)的表达.结果 显示,罗格列酮治疗可降低糖尿病大鼠增高的肾脏重量/体重比值、肌酐、尿素氮、尿蛋白排泄率、甘油三酯水平(均P＜0.01).罗格列酮增加糖尿病大鼠肾脏降低的PEDF、MMP-2蛋白表达,降低升高的TGF-β1蛋白表达(均P＜0.01).PEDF mRNA的表达也呈相似趋势.提示罗格列酮可通过调节肾脏PEDF、MMP-2及TGF-β1的表达对肾脏起到保护作用.

Abstract：

Forty-five male SD rats were divided into normal group, diabetic control group, and rosiglitazone treatment diabetic group.By the end of 12 weeks, the expressions of pigment epithelium-derived factor(PEDF), matrix metalloproteinase-2 (MMP-2), and transforming growth factor-β1 (TGF-β1) in the kidney were determined by immunohistochemistry and RT-PCR.The results showed that rosiglitazone decreased the increased kidney weight/body weight ratio, serum creatinine, blood ureanitrogen, urinary albumin excretion, triglyceride levels in diabetic rats (all P＜0.01).Rosiglitazone prevented the decreasing of protein expressions of PEDF and MMP-2 and the increasing of protein expression of TGF-β1 (all P＜0.01).PEDF mRNA showed a similar change,suggesting that renoprotection of rosiglitazone on diabetic rats may be mediated through regulating the expressions of PEDF, MMP-2, and TGF-β1.     

罗格列酮对糖尿病大鼠肾脏PEDF和TGF-β1表达的影响

目的探讨罗格列酮（RGZ）对DM大鼠肾组织色素上皮衍生因子（PEDF）和转化生长因子β1（TGF-β1）的影响。方法SD大鼠随机分为NC组、DM组和RGZ干预组（RGZ组）。12周后,观察各组FBG、肾重、肾重／体重指数、血脂,24小时UA1b的变化,以及肾脏组织标本行免疫组化和Westernblot观察PEDF和TGF-β1的表达。结果（1）RGZ组大鼠FBG、肾重、肾重／体重、24小时UA1b、Cr,BUN均低于DM组。（2）免疫组化及Westernblot显示,DM组和RGZ组肾组织TGF-β1表达均高于NC组（P〈0．01,P＜0．05）,而RGZ组TGF-β1低于DM组（P〈0．01）;DM组和RGZ组PEDF均低于NC组（P〈0．01,P＜0．05）,而RGZ组PEDF高于DM组（P〈0．05）。结论RGZ通过减低DM大鼠肾脏TGF-β1和升高PEDF的表达,对肾脏起到保护作用。     

Effect of octreotide and insulin on manifest renal and glomerular hypertrophy and urinary albumin excretion in long-term experimental diabetes in rats

Summary Treatment of diabetic rats with octreotide can inhibit early diabetic renal hypertrophy. Octreotide administration for 6 months from the day of diabetes induction inhibits renal hypertrophy and diminishes increase in urinary albumin excretion. To investigate the effect of octreotide on manifest diabetic renal changes, octreotide treatment was given for 3 weeks after an untreated diabetic period of 3 or 6 months. In addition, following 6 months of diabetes, a group of diabetic rats was treated with insulin for 3 weeks. Renal and glomerular hypertrophy, and increased urinary albumin excretion were observed in diabetic rats compared to non-diabetic control rats from 3 months and throughout the study period. Octreotide treatment did not affect body weight, food intake, blood glucose or serum fructosamine levels. We observed no effect of octreotide treatment on renal and glomerular hypertrophy or urinary albumin excretion compared to placebotreated diabetic rats. Insulin treatment for 3 weeks after 6 months of untreated diabetes normalized blood glucose and serum fructosamine levels, and furthermore renal hypertrophy was significantly diminished compared to the placebo-treated diabetic rats. However, insulin treatment had no effect on glomerular hypertrophy or urinary albumin excretion. In conclusion, octreotide treatment for 3 weeks following an untreated diabetic period of 3 or 6 months is unable to reduce the increased renal and glomerular volume or urinary albumin excretion. However, insulin treatment for 3 weeks with induction of euglycaemia diminishes the renal hypertrophy but has no effect on glomerular volume or urinary albumin excretion.Abbreviations UAE Urinary albumin excretion - IGF-I insulin-like growth factor I - IGFBP insulin-like growth factor binding protein - STZ streptozotocin - TGV total glomerular volume - BW body weight - GH growth hormone - RPF renal plasma flow     

不同尿白蛋白水平的糖尿病患者单核细胞趋化蛋白-1和尿N-乙酰β-D-氨基葡萄糖苷酶的含量变化及其临床意义

目的观察不同尿白蛋白水平的糖尿病患者单核细胞趋化蛋白1(MCP1)和尿N乙酰βD氨基葡萄糖苷酶(NAG)的含量变化及其临床意义。方法将60例糖尿病患者按尿白蛋白排泄率(UAER)的不同分为正常白蛋白尿组、微量白蛋白尿组和大量白蛋白尿组3组。分别测定血清和尿MCP1的含量、尿NAG含量以及血肌酐(Scr)、糖化血红蛋白(GHbAlc),进行组间比较,并与对照组比较,同时做尿MCP1与GHbAlc、UAER、NAG的相关分析。结果尿MCP1含量及NAG含量在所有患者中均升高,明显高于对照组,且大量白蛋白尿组升高最明显,其升高程度与尿白蛋白排泄率增高程度一致,即随糖尿病肾病加重而逐渐升高。而血清MCP1水平较低,与对照组比较无显著性差异;尿MCP1与GHbAlc、UAER、NAG呈正相关关系。结论尿中MCP1升高与糖尿病肾病的发生发展有密切关系,尤其与肾小管间质损伤有更密切的关系。     

山莨菪碱与卡托普利对糖尿病肾病的影响

以放射免疫测定法检测尿白蛋白，筛选出糖尿病肾病４７例（其中早期４０例，临床期７例），随机分成两组，采用自身对照试验比较山莨菪碱与卡托普利对糖尿病肾病的影响。结果显示：山莨菪碱和卡托普利治疗４周后，患者有效肾血浆流量上升，肾小球滤过分数下降，而肌酐清除率无明显变化；尿白蛋白平均下降４９ｍｇ／ｄ（Ｐ＜０．０１）与５７ｍｇ／ｄ（Ｐ＜０．００５）：这表明山莨菪碱具有与卡托普利类似的降低尿蛋白和改善肾功能的作用。     

N-乙酰半胱氨酸对糖尿病大鼠肾脏NADPH氧化酶表达的影响

目的探讨N-乙酰半胱氨酸（NAC）对糖尿病大鼠肾脏尼克酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶表达的影响。方法大鼠随机分为正常对照（NC）组、正常对照NAC治疗组（CT组）、糖尿病组（DM组）和糖尿病NAC治疗组（DT组）。8周后测定血糖、胰岛素、肌酐、游离15-F2t-异前列烷和总抗氧化物水平、24小时尿蛋白排泄量（UPro/24h）、肾系膜基质增宽指数、肾皮质p22phox、p67phox、铜-锌-超氧化物歧化酶（Cu-Zn-SOD）和结缔组织生长因子（CTGF）蛋白表达。结果糖尿病大鼠UPro/24h、血浆游离15-F2t-异前列烷水平、系膜基质增宽指数、肾脏p22phox、p67phox和CTGF蛋白表达显著增高，血浆总抗氧化物浓度和肾脏Cu-Zn-SOD蛋白表达显著降低。NAC治疗能显著逆转糖尿病大鼠上述各项指标的变化。结论NAC显著降低糖尿病大鼠肾脏氧化应激水平，减轻氧化应激对肾组织的损伤，产生肾脏保护作用。     

血管紧张素受体拮抗剂缬沙坦对糖尿病大鼠肾脏的保护作用

探讨血管紧张素受体拮抗缬沙坦对糖尿病大鼠肾脏病变的保护作用及其机制。方法将实验动物分为正常对照组,糖尿病组及缬沙坦疗组。检测各组第２、４、８周的平均动脉压,血糖、血胰岛素,血肌酐、尿白蛋白、肾组织血管紧张素转换酶活性、血管紧张素Ⅱ含量及肾脏肥大指标的变化。     

糖基化产物对正常大鼠尿蛋白排泄和肾脏结构的影响

目的为探讨糖基化产物对正常肾脏的特异性损害作用。方法正常大鼠静脉注射体外制备的糖基化血清蛋白（ＧＳＰ），为期２个月，观察ＧＳＰ对大鼠尿蛋白排泄、肾皮质糖基化产物和肾脏形态的影响。结果接受ＧＳＰ的大鼠血清和肾组织中糖基化终产物（ＡＧＥｓ）水平、肾小球硝基四氮唑蓝（ＮＢＴ）染色强度、尿蛋白排泄量和尿量均明显高于对照组。光学和电子显微镜观察显示，给予ＧＳＰ的大鼠肾小球体积明显增大，肾小球系膜区扩大伴有细胞外基质增加，ＰＡＳ阳性物质沉着增多和肾小球基底膜节段性增厚。结论糖基化产物能引起类似糖尿病肾病的肾脏损害。     

膜性肾病患者尿蛋白成分与临床及病理的相关性分析

目的 探讨膜性肾病（MN）患者尿中N-乙酰-β-D-氨基葡萄糖苷酶（NAG）、视黄醇结合蛋白（RBP）、白蛋白（ALB）、免疫球蛋白G（IgG）、补体C3的构成特点及其与临床和病理的关系.方法 收集原发性膜性肾病患者95例,测定患者尿液中NAG、RBP、ALB、IgG及C3的浓度,并与各项临床及病理指标进行统计分析.结果 51 ～ 70岁年龄组患者尿RBP、IgG及C3含量较14～ 20岁组明显升高（P＜0.05）.血压升高组较血压正常组各种尿蛋白成分浓度均明显升高（P＜0.05）.肾功能不全组患者的尿NAG、RBP、ALB及IgG及补体C3水平均高于肾功能正常组（P＜0.05）.伴镜下血尿组患者尿RBP、ALB及IgG较不伴镜下血尿组明显增高（P＜0.05）.随着病理分期进展,患者尿NAG、RBP、IgG和C3等浓度明显升高（P＜0.05）;随着小管间质损害的加重,尿NAG、IgG和C3浓度均明显升高（P＜0.05）.结论 膜性肾病患者尿NAG、RBP、ALB、IgG及C3检测可以反映患者的病情,提示肾脏病理损害程度.     

厄贝沙坦对糖尿病大鼠肾脏GluT-1及TGF-β1表达的影响及其临床意义

目的观察厄贝沙坦（IBST）对糖尿病大鼠肾脏皮质葡萄糖转运蛋白-1（GluT-1）及转化生长因子-β1（TGF-β1）表达的影响,并探讨其作用机制。方法48只大鼠随机分为对照（Con）组、糖尿病（DM）组与IBST治疗组,建立糖尿病肾病（DN）模型,分别检测肾皮质GluT-1 mRNA及TGF-β1 mRNA表达水平。结果与Con组相比,DM组大鼠肾组织GluT-1 mRNA表达及TGF-β1 mRNA表达均显著上调（P〈O．01）。厄贝沙坦干预后,IBST组肾组织GluT-1及TGF-β1 mRNA表达显著低于DM组（P〈0.01）。结论厄贝沙坦对DN有保护作用,这可能与厄贝沙坦显著降低肾组织GluT-1及TGF-β1 mRNA表达有关。     

The effect of simvastatin on the serum monocyte chemoattractant protein-1 and intracellular adhesion molecule-1 levels in diabetic rats

ObjectiveThis study aimed to observe the effect of simvastatin on the serum monocyte chemoattractant protein-1 (MCP-1) and intracellular adhesion molecule-1 (ICAM-1) levels and to probe its protective mechanisms on macroangiopathy in diabetic rats.MethodsTwenty-four Wistar rats were randomly assigned to a normal control group (Group A, n=8), and STZ-induced diabetic group (Group B, n=8), or a simvastatin-treated diabetic group (Group C, n=8). Rats in Group C were treated with simvastatin (20 mg kg^?1 day^?1) 1 week after the establishment of the diabetic model. Groups A and B were treated with corresponding sodium chloride. Peripheral blood glucose was tested weekly; serum MCP-1, ICAM-1, and HbA1c levels were tested at the eighth week.ResultsAt the second, fourth, and eighth week, peripheral blood glucose levels in Group B were similar to those of Group C, which were much higher than those of Group A. Serum MCP-1 and ICAM-1 levels in Groups B and C were higher than those of Group A (P<.01), and serum MCP-1 and ICAM-1 levels in Group C were lower than those of Group B (P<.01); HbA1c was not significantly different between Group C and Group B.ConclusionSimvastatin has the effect of anti-inflammation, which may play some protection against the progress of atherosclerosis in diabetic rats.     

人组织激肽释放酶对糖尿病肾病大鼠的影响

目的：探讨基因重组人组织激肽释放酶（KLK）对大鼠糖尿病肾病的影响。方法：大鼠经链脲佐菌素诱导制成糖尿病（DM）模型于第8、12、16周留取尿标本。比色法检测大鼠血浆KLK变化，放射免疫技术、酶联免疫吸附试验（ELISA）、免疫组化技术测定肾组织一氧化氮（NO）、环磷腺苷（cAMP）、血内皮素1（ET-1）变化及光镜电镜观察肾组织形态改变。结果：（1）DM组与正常对照组（C）组大鼠比较，体重（BW）、血浆KLK活性、肾组织中NO、cAMP含量下降（P〈0．01或P〈0．05）。而DM组的血糖（BG）、血肌酐、血尿素氮（BUN）、肾重（KW）体重比值、ET-1、尿白蛋白（Ualb）排泄率、24h尿蛋白定量均高于（NC）组（P〈0．01或P〈0．05）。（2）糖尿病KLK治疗组（DK）组与NC组大鼠比较，BW、血浆KLK活性、肾组织中NO、cAMP含量下降（P〈0．01或P〈0．05）；而BG、KW／BW、Ualb排泄率、24h尿蛋定量均高于c组（P〈0．01或P〈0．05）。DM组、DK组间BG、BUN、BW、KW／BW无显著性差异，血浆KLK活性、肾组织中NO、cAMP含量，DK组明显高于DM组（P〈0．01或P〈0．05）。而血肌酐、Ualb排泄率、24h尿蛋白定量则显著低于DM组（P〈0．01或P〈0．05）。（3）①16周时，DM组血浆KLK活性明显低于8周时的水平（P〈0．01），明显较NC组降低（P〈0．01）；而DK组血浆KLK活性明显高于8周时的水平（P〈0．05），该组病变较DM组轻。②DK组12周、16周尿白蛋白排泄率均低于8周时的水平（P〈0．05），16周时，DK和DM比较尿白蛋排泄率差异显著（P〈0．05）。③16周时，DM组肾组织中NO、cAMP含量则明显低于C组（P〈0．01），而与DM组相比，DK组肾组织中NO、cAMP含量较高（P〈0．01或P〈0．05）。结论：给予外源性人组织KLK可抑制糖尿病大鼠肾小球系膜细胞增殖、基质增多，可使尿蛋白排泄减少，延缓糖尿病肾病的发展。     

Attenuation of diabetic nephropathy in diabetes rats induced by streptozotocin by regulating the endoplasmic reticulum stress inflammatory response

The endoplasmic reticulum (ER) is capable of sensing metabolic and stress parameters and integrating intra- and extracellular signals to support a coordinated cell response. In the present study, we verified the hypothesis that 4-phenylbutyric acid (4-PBA), a chemical chaperone, prevented the progression of diabetic nephropathy (DN). Male Sprague-Dawley rats were randomly divided into 3 groups: a normal control group, a DN group, and a DN model plus 4-PBA treatment group (PBA). The DN model was induced by injection of streptozotocin with uninephrectomy. The dosage of 4-PBA treatment was gavaged at a dose of 1 g/kg body weight each day for 12 weeks. The expression of the ER stress indicators significantly increased in the kidney of DN rats within the indicated period. Moreover, the expression of phosphorylated c-JUN NH₂-terminal kinase, the monocyte chemoattractant protein-1, and the final fibrotic effector all elevated markedly in the kidney of DN rats. Urinary protein excretion rate and the concentration of urinary monocyte chemoattractant protein-1 were higher than those in the normal control group. Treatment with 4-PBA can suppress the expression of the glucose-regulated protein 78 and the phosphorylation of the PKR-like ER kinase, both of which are ER stress indicators; renoinflammatory signal; and the expression of inflammatory cytokines and fibrosis factors. It also can inhibit the increase in urinary protein excretion rate and urinary monocyte chemoattractant protein-1. In conclusion, 4-PBA exerts a marked renoprotective effect possibly due to modulating ER stress and related inflammatory cascade.