Han K H, Kang Y S, Han S-Y, Jee Y H, Lee M H, Han J Y, Kim H K, Kim Y S, Cha D R
Department of Internal Medicine, Korea University, Ansan City, Kyungki-Do, Korea.
Kidney Int. 2006 Jul;70(1):111-20. doi: 10.1038/sj.ki.5000438. Epub 2006 May 24.
Administration of spironolactone provides a beneficial effect in various animal models of renal injury. In this study, we investigated whether spironolactone prevents the progression of diabetic nephropathy through reduction of connective tissue growth factor (CTGF) synthesis in type II diabetic rats. In addition, we evaluated the effect of aldosterone and spironolactone on CTGF and collagen production in cultured cells. Renal functional and morphologic changes were examined in Otsuka Long-Evans Tokushima Fatty rats with or without spironolactone treatment (20 mg/kg/day) for 8 months, as well as in non-diabetic age-matched Long-Evans Tokushima Otsuka rats. Spironolactone treatment did not induce any significant differences in body weight, kidney/body weight ratio, serum creatinine concentration, blood glucose levels, or systolic blood pressure. However, urinary protein and albumin excretion were significantly decreased in the spironolactone treatment group, which was associated with amelioration of glomerulosclerosis. In addition, renal CTGF, collagen synthesis demonstrated marked decreases in the spironolactone treatment group. In cultured MC and PTC, aldosterone induced significant increases in CTGF gene expression and protein synthesis associated with increased collagen synthesis, which was abolished by prior treatment with spironolactone. However, aldosterone treatment did not induce transforming growth factor (TGF)-beta1 overproduction, and inhibition of TGF-beta1 by neutralization of TGF-beta1 protein did not significantly prevent aldosterone-induced CTGF production. These results suggest that the antifibrotic effects of spironolactone may be mediated by CTGF through a TGF-beta1-independent pathway in this animal model of diabetic nephropathy.
给予螺内酯在各种肾损伤动物模型中均产生有益作用。在本研究中，我们调查了螺内酯是否通过减少II型糖尿病大鼠结缔组织生长因子（CTGF）的合成来预防糖尿病肾病的进展。此外，我们评估了醛固酮和螺内酯对培养细胞中CTGF和胶原蛋白产生的影响。对大冢长-伊万科-德岛肥胖大鼠进行或不进行螺内酯治疗（20mg/kg/天）8个月，以及对非糖尿病且年龄匹配的大冢长-伊万科-德岛大鼠进行肾功能和形态学变化检查。螺内酯治疗在体重、肾重/体重比、血清肌酐浓度、血糖水平或收缩压方面未引起任何显著差异。然而，螺内酯治疗组的尿蛋白和白蛋白排泄显著减少，这与肾小球硬化的改善相关。此外，螺内酯治疗组的肾CTGF、胶原蛋白合成显著减少。在培养的系膜细胞（MC）和近端小管细胞（PTC）中，醛固酮诱导CTGF基因表达和蛋白合成显著增加，同时胶原蛋白合成增加，而预先用螺内酯治疗可消除这种增加。然而，醛固酮治疗未诱导转化生长因子（TGF）-β1过量产生，通过中和TGF-β1蛋白抑制TGF-β1并不能显著预防醛固酮诱导的CTGF产生。这些结果表明，在该糖尿病肾病动物模型中，螺内酯的抗纤维化作用可能通过CTGF由一条不依赖TGF-β1的途径介导。
