胰岛素样生长因子1受体抑制剂可减轻糖尿病肾病小鼠肾小管病变

目的探讨胰岛素样生长因子1受体(IGF-1R)抑制剂在缓解糖尿病肾病(DKD)小鼠肾小管病变中的作用。方法C57BL/6J雄性小鼠被随机分为正常对照组(n=10)和DKD模型组(n=30)。用单次腹腔注射链脲佐菌素(STZ,150 mg/kg)的方法建立糖尿病肾病模型。建模成功后,DKD模型组小鼠被随机分为DKD组(n=10)、贝那普利组(n=10)和IGF-1R抑制剂组(n=10)。IGF-1R抑制剂组给予30 mg·kg-1·d-1 IGF-1R抑制剂灌胃;贝那普利组给予30 mg·kg-1·d-1贝那普利灌胃;正常对照组和DKD组分别给予等量生理盐水灌胃。8周后处死小鼠,记录小鼠体重、肾重。收集小鼠血清、尿液和肾脏样本。自动生化仪上测定血糖、尿白蛋白等生化指标,计算尿白蛋白排泄率。HE、PAS染色法观察小鼠肾脏病理改变。免疫组化、Western印迹法测定肾组织磷酸化(p)IGF-1R的表达。结果与正常对照组比较,DKD组小鼠的随机血糖、肾重/体重、尿白蛋白排泄率明显升高(均P<0.01)。DKD组小鼠肾脏病理表现为肾小球增大,肾小管管腔狭窄,肾小管肿胀、萎缩;近端小管上皮(PTE)细胞数目减少,肾小管损伤评分增加,平均肾小球体积增大,肾组织pIGF-1R表达增加(均P<0.05)。与DKD组相比,IGF-1R抑制剂组和贝那普利组小鼠尿白蛋白排泄率显著降低(P<0.01),肾脏病理改变减轻,且IGF-1R抑制剂组的作用效果更加显著。与DKD组相比,IGF-1R抑制剂组肾组织pIGF-1R蛋白表达减少(P<0.05);与贝那普利组相比,IGF-1R抑制剂组肾组织pIGF-1R蛋白表达减少(P<0.05)。结论IGF-1R抑制剂能减轻DKD小鼠肾小管病变,且效果优于贝那普利。

Insulin-like growth factor-1 receptor inhibitor alleviates diabetic kidney disease mouse tubulopathy

Objective To investigate the effects of insulin-like growth factor 1 receptor(IGF-1R)inhibitor on tubulopathy in diabetic kidney disease(DKD)mice.Methods C57BL/6J male mice were randomly divided into normal control group(n=10)and DKD model group(n=30),by giving a single intraperitoneal injection of STZ 150 mg/kg to establish a DKD model.After established successfully,the mice in DKD model group were randomly divided into DKD group(n=10),benazepril group(n=10)and IGF-1R inhibitor group(n=10).IGF-1R inhibitor group was given intraperitoneal injection of IGF-1R inhibitor(30 mg·kg-1·d-1)and benazepril group was given intraperitoneal injection of benazepril(30 mg·kg-1·d-1).Normal control group and DKD group were given an equal amount of normal saline.After 8 weeks of feeding,mice were euthanatized.Body weight and kidney weight were recorded.Blood,urine and kidney samples were collected.Biochemical tests such as blood glucose and urine albumin were measured by automatic biochemical instruments and albumin excretion rate was calculated.Pathological changes of mice were observed by hematoxylin-eosin staining(HE)and periodic acid-schiff staining(PAS).Phosph(p)IGF-1R expression level was determined by immunohistochemistry and Western blotting.Results Compared with the normal control group,blood glucose,kidney weight/body weight and urinary albumin excretion rate were significantly higher in DKD group(all P<0.01).In DKD mice,glomerular expansion,tubular stenosis,tubular swelling and tubular atrophy were significantly detected.Meanwhile,the number of proximal tubular epithelial(PTE)cells was decreased,and the renal tubular injury scores,the average glomerular volume,and pIGF-1R protein expression were increased(all P<0.05).Compared with the DKD group,albumin excretion rate was significantly reduced(P<0.01),the above pathological changes were alleviated and the effect of IGF-1R inhibitor was more significant.Compared with the DKD group,the pIGF-1R protein expression was reduced in IGF-1R inhibitor group(P<0.05).Compared with the benazepril group,the pIGF-1R protein expression was reduced in IGF-1R inhibitor group(P<0.05).Conclusion IGF-1R inhibitor has better effect than benazepril on alleviating the tubulopathy of DKD mice.