Cha Dae Ryong, Kang Young Sun, Han Sang Youb, Jee Yi Hwa, Han Kum Hyun, Kim Hyoung Kyu, Han Jee Young, Kim Young Sik
Department of Internal Medicine, Korea University, Ansan City, Kyungki-Do, Korea.
Nephrology (Carlton). 2005 Oct;10 Suppl:S37-9. doi: 10.1111/j.1440-1797.2005.00455.x.
In the last 10 years, many studies have focused on the non-classical action of aldosterone. One of the most important new aspects of aldosterone is its pathogenic role as proinflammatory and profibrotic molecules. It has been reported that aldosterone induces myocardial fibrosis and vascular inflammation through up-regulation of various proinflammatory and profibrotic cytokines. We investigated the effect of aldosterone and spironolactone, which is a non-selective mineralocorticoid receptor antagonist, on monocyte chemoattractant peptide (MCP-1) and collagen synthesis in cultured mesangial and tubular epithelial cells. In addition, to evaluate the effect of spironolactone on diabetic nephropathy, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats which are known type 2 diabetic animal models. Spironolactone treatment did not induce any significant change in blood glucose levels and blood pressure. However, spironolactone therapy significantly inhibited urinary albumin and MCP-1 excretion. Spironolactone treatment also suppressed renal mRNA expression for MCP-1, macrophage migration inhibitory factor (MIF) as well as intrarenal protein synthesis for ED-1 and MIF. Morphologically, spironolactone treatment significantly prevented glomerulosclerosis, collagen deposition and connective tissue growth factor (CTGF) expression in diabetic rats. In cultured cell experiments, aldosterone directly increased the MCP-1, collagen secretion and spironolactone treatment abolished aldosterone-induced MCP-1 and collagen synthesis. Surprisingly, aldosterone treatment did not induce any significant change in TGFbeta1 gene transcription. Finally, we found that NF-kB activity was increased after stimulation with aldosterone and spironolactone therapy inhibited their activation. In addition, prior treatment with pyrrolidine dithiocarbamate (PDTC), which is a NF-KB inhibitor, inhibited aldosterone-induced MCP-1 protein secretion. These results suggest that aldosterone blockade could play a role in preventing the progression of diabetic nephropathy via anti-inflammatory and antifibrotic mechanisms.
在过去十年中，许多研究聚焦于醛固酮的非经典作用。醛固酮最重要的新特性之一是其作为促炎和促纤维化分子的致病作用。据报道，醛固酮通过上调多种促炎和促纤维化细胞因子诱导心肌纤维化和血管炎症。我们研究了醛固酮和非选择性盐皮质激素受体拮抗剂螺内酯对培养的系膜细胞和肾小管上皮细胞中单核细胞趋化蛋白（MCP - 1）和胶原蛋白合成的影响。此外，为评估螺内酯对糖尿病肾病的作用，我们使用了已知的2型糖尿病动物模型大冢长 - Evans 德岛肥胖（OLETF）大鼠。螺内酯治疗未引起血糖水平和血压的任何显著变化。然而，螺内酯治疗显著抑制尿白蛋白和MCP - 1排泄。螺内酯治疗还抑制了肾脏中MCP - 1、巨噬细胞迁移抑制因子（MIF）的mRNA表达以及肾内ED - 1和MIF的蛋白质合成。形态学上，螺内酯治疗显著预防了糖尿病大鼠的肾小球硬化、胶原蛋白沉积和结缔组织生长因子（CTGF）表达。在培养细胞实验中，醛固酮直接增加MCP - 1、胶原蛋白分泌，而螺内酯治疗消除了醛固酮诱导的MCP - 1和胶原蛋白合成。令人惊讶的是，醛固酮治疗未引起TGFβ1基因转录的任何显著变化。最后，我们发现醛固酮刺激后NF - kB活性增加，而螺内酯治疗抑制了它们的激活。此外，用NF - KB抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）预处理可抑制醛固酮诱导的MCP - 1蛋白分泌。这些结果表明，醛固酮阻断可能通过抗炎和抗纤维化机制在预防糖尿病肾病进展中发挥作用。
