蛋白酶体抑制剂对糖尿病肾病大鼠的治疗作用

Effect of proteasome inhibitor on diabetic nephropathy in rats

目的糖尿病肾病(diabetic nephropathy,DN)是一种高糖刺激的炎症性疾病,泛素蛋白酶体是调节炎症细胞因子关键转录因子NF-kB的上游信号系统,拟探讨蛋白酶体抑制剂MG-132对大鼠DN的治疗作用。方法 54只成年SD雄性大鼠随机分为正常对照(normal control,NC)组、糖尿病肾病模型(diabetic nephropathy,DN)组、MG-132治疗组。分别在药物干预的4、8、12周时测定大鼠体重(body weight,BW)、肾重(kidney weight,KW)及体重/肾重指数(kidney weight/body weightindex,KI)、血糖(glucose,Glu)、三酰甘油(triglycerides,TG)、总胆固醇(total cholesterol,TC)、24h尿蛋白排泄率(urinary albuminexcretion rate,UAER),同时观察肾脏病理学改变。结果①与NC组比较,DN大鼠的Glu、TG、TC、24 hUAER均明显升高(P<0.05)。MG-132治疗可显著降低大鼠的Glu水平、显著减少24 hUAER(P<0.05),TG、TC也显著降低(P<0.05)。②与NC组大鼠比较,DN组大鼠KW明显增加,KI显著增大(P<0.05)。MG-132治疗后KI明显下降(P<0.05)。③MG-132治疗DN大鼠的肾脏病理表现,如肾小球基底膜增厚,系膜细胞增生、系膜基质积聚,得以减轻。系膜细胞和肾小管上皮细胞表达α平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)明显减少。结论泛素蛋白酶体途径(ubiquitin proteasome pathway,UPP)可能是治疗DN的有效药物靶点。

Objective It is well-known that diabetic nephropathy is an sub-inflammatory diseasse,which is stimulated by high-glucose.Ubiquitin-proteasome system plays an important role on regulating the upstream of transcription factor NF-kB signaling system.Therefore,this study was to investigate the effect of proteasome inhibitor MG132 on diabetic nephropathy in rats.Methods Fifty-four male SD rats were randomly divided into three groups,which were normal control group（NC）,diabetic nephropathy group（DN）and diabetic nephropathy treated with MG-132 group（MG132）.At the end of 4,8 and 12 weeks,body weight（BW）,kidney weight（KW） and kidney weight/ body weight index（KI）of rats were measured and calculated.Serum biochemical parameter and 24 h urinary albumin excretion rate（UAER）were also detected by autoanalyzer of biochemistry.Results ①DN and MG-132 rats,the level of blood glucose,triglycerides,total cholesterol,24 h urinary protein excretion rate were significantly higher（P0.05）,compared with NC group.The level of blood glucose and 24 h urinary albumin excretion rate decreased significantly in MG132 group,compared with DN group.②Compared with NC rats,DN rats decreased body weight,and a marked increase in kidney weight,correspondingly,kidney weight / body weight ratio significantly increased（P0.05）.Treatment by MG132 could reverse the alteration partially（P0.05）.③ In MG132 group,pathological changes of the kidney,such as glomerular basement membrane thickening,mesangial cell proliferation,accumulation of mesangial matrix alleviated were alleviated.The expression of α-smooth muscle actin（α-SMA）in mesangial cells and renal tubular epithelial cell decreased significantly.Conclusion Ubiquitin-proteasome pathway may be an effective drug target for treating diabetic nephropathy.