FK506对糖尿病大鼠早期肾脏肥大的抑制作用及机制

Inhibition of FK506 on renal hypertrophy and its mechanism in early diabetic rats induced by streptozotocin

目的 探讨FK506对糖尿病大鼠早期肾脏肥大的抑制作用及机制。方法 应用链脲菌素（65mg／kg）腹腔注射建立大鼠糖尿病模型。每日分别给予FK506 0．5、1．0mg／kg灌胃，共4周。观察大鼠肾质量／体质量、尿白蛋白排泄率（AER）、Ccr及肾组织病理形态学变化。应用Western印迹和免疫组化方法检测肾组织钙神经蛋白（calcineurin，CaN）、1αⅣ型胶原、α-平滑肌肌动蛋白（α-SMA）及转化生长因子β1（TGF-β1）蛋白表达。结果 FK5061．0组大鼠相对肾质量明显低于模型组（P〈0．05）。FK5060．5与1．0组大鼠AER水平与肾小球平均体积明显低于模型组（P〈0．05、0．01）。FK5061．0组肾小管间质-损伤指数也明显低于模型组（P〈0．01）。Western印迹显示，模型组肾组织CaN蛋白表达较对照组增加2．4倍；FK5060．5与1．0组肾组织CaN蛋白表达比模型组下降38．0％与73．2％。模型组肾组织1仅Ⅳ型胶原、α-SMA及TGF-β1蛋白表达明显高于对照组；FK506组肾组织上述蛋白表达明显低于模型组（P〈0．05、0．01）。结论 FK506对糖尿病大鼠早期肾脏肥大有明显抑制作用，其机制与下调肾组织增高的CaN表达有关。

Objective To study the effect of FK506 on renal hypertrophy and its mechanism in early diabetic rats. Methods Diabetes was induced with streptozotocin in rats, and FK506 （0.5 or 1.0 mg/kg） was orally administered once a day for 4 weeks. Relative kidney weight （RKW）, 24-hour urinary albumin excretion rate （AER） and creatinine clearance rate （Ccr） were measured. Kidney pathology was observed by light microscopy. The expression of calcineurin （CAN）, 1α type Ⅳ collagen, α-smooth muscle actin （α-SMA） and transforming growth factor β1 （TGF-β1） were determined by Western blot or immunohistochemistry. Results Increased RKW was significantly reduced by FK506 treatment with 1.0 mg/kg （P 〈 0.05）. Elevated AER was markedly attenuated by FK506 treatment with 0.5 and 1.0 mg/kg （P 〈 0.05, 0.01）. Ccr in diabetic rat was not changed by FK506 treatment with 0.5 or 1.0 mg/kg. Elevated glomerular volume was significantly attenuated by FK506 treatment with 0.5 and 1.0 mg/kg （P 〈 0.05）, and increased indices for tubulointerstitial injury were only ameliorated by FK506 treatment with 1.0 mg/kg （P 〈0.01）. Western blot analysis demonstrated that the expression of CaN protein was increased by 2.4 folds in the kidney of diabetic rats as compared to controL, and FK506 treatment with 0.5 and 1.0 mg/kg could reduce the increased expression of CaN protein by 38.0% and 73.2%. The expression levels of 1α type IV collagen, α-SMA and TGF-β1 protein in the kidney were significantly increased in diabetic rats and decreased by FK506 treatment （P 〈 0.05, 0.01）. Conclusion FK506 can inhibit early renal hypertrophy in diabetic rats, whose mechanism may be at least partly associated with down-regulation on increased expression of CaN in the kidney of diabetic rats.