L-158809对2型糖尿病大鼠模型肾脏保护的机制探讨  

Renoprotective properties of L-158809 in type 2 diabetic rat model

作　　者：段文澜[1] 方京冲[1] 杨秀芳[1] 史虹莉[1] 张志刚[2] 陈广平[2] 郭慕依[2] 

机构地区：[1]复旦大学附属华山医院糖尿病研究室,上海200040 [2]复旦大学基础医学院病理解剖教研室

出　　处：《中华内分泌代谢杂志》2001年第6期374-377,T002,共5页Chinese Journal of Endocrinology and Metabolism

摘　　要：目的　观察血管紧张素Ⅱ (ATⅡ )受体拮抗剂L 15 880 9对 2型糖尿病大鼠模型肾脏的保护作用 ,并探讨其作用机制。方法　 2型糖尿病大鼠在L 15 880 9治疗 16周后 ,测定肾组织ATⅡ含量 ,利用组织学检查观察肾组织结构的改变 ,免疫组化观察基质金属蛋白酶 2 (MMP 2 )及其金属蛋白酶 2组织抑制剂 (TIMP 2 )在肾小球的表达 ,酶谱法测定肾皮质MMP 2的活性 ,Western印迹检测肾皮质TIMP 2的含量。结果　L 15 880 9治疗使糖尿病大鼠血浆和肾皮质ATⅡ浓度进一步升高 ,肾小球基质增生明显减轻 ,肾小球MMP 2染色强度和肾皮质MMP 2的活性增强 ,但不能使肾小球TIMP 2染色及肾皮质TIMP 2含量降至正常。结论　L 15 880 9对类似人类 2型糖尿病大鼠肾脏病变有保护作用 ,对肾脏细胞外基质沉积的改善部分是通过促进基质转化而实现的。Objective To observe the renoprotective effects of angiotensin Ⅱ (ATⅡ) receptor antagonist, L-158809 and to explore its potential mechanisms. Methods The experimental rats consisted of normal control and type 2 diabetic model groups with or without treatment of L-158809 (2 mg·kg -1 ·d -1 ) for 16 weeks. Blood glucose, HbA 1c , serum immunoreactive insulin, serum creatinine, mean arterial blood pressure, creatinine clearance (Ccr) and urinary albumin excretion index (UAEI) as well as plasma and renal ATⅡ content were measured. The kidney morphological changes were examined by renal histopathology. Marix metalloproteinase-2 (MMP-2) and the tissue inhibitor of metalloproteinase-2 (TIMP-2) expression in renal tissues were studied by immunohistochemistry, zymography and Western blot. Results In type 2 diabetic rats, L-158809 restored the blood pressure (P<0.05), Ccr (P<0.01) and UAEI (P<0.01) to normal level, increased the plasma and renal content of ATⅡmarkedly (P<0.001 and P<0.01) and alleviated the accumulation of extracellular matrix (ECM) (P<0.01). Meanwhile L-158809 enhanced the MMP-2 staining intensity in glomeruli by 2.2 times (P<0.01) and improved the gelatinolytic activities of MMP-2 in renal cortex by 85% (P<0.01), whereas TIMP-2 staining in glomeruli as well as TIMP-2 content in renal cortex still remained high. Conclusion L-158809 exerts beneficial effects on kidneys of type 2 diabetic rats. Improved ECM turnover and degradation may contribute to the ameliorative effect of L-158809 on the accumulation of ECM in glomeruli.

关 键 词：Ⅱ型糖尿病 细胞外基质 基质金属蛋白酶2 金属蛋白酶2组织抑制剂 血管紧张素受体 

分 类 号：R587.2[医药卫生—内分泌] R692[医药卫生—内科学]