Fluvastatin prevents nephropathy likely through suppression of connective tissue growth factor-mediated extracellular matrix accumulation
Fluvastatin prevents nephropathy likely through suppression of connective tissue growth factor-mediated extracellular matrix accumulation
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DOI：
10.1016/j.yexmp.2003.08.002
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发表时间：
2004-02-01
影响因子：
3.6
通讯作者：
Cai, L
中科院分区：
文献类型：
--
作者：
Song, Y;Li, C;Cai, L
糖尿病肾病与肾小球细胞外基质（ECM）积聚导致肾小球硬化有关。氟伐他汀作为降脂药可以显着预防糖尿病肾病，可能不仅是通过其降脂作用，而且主要是通过其直接抑制肾小球ECM的积累。为了验证这一假设，在本研究中，采用六分之五肾切除（5/6Nx）大鼠模型来诱导肾ECM积聚而不同时存在高脂血症，以研究氟伐他汀对肾功能、肾小球ECM积聚和结缔组织生长因子（CTGF）表达的影响。 5/6Nx 在 13 周时诱导大鼠出现明显的肾病，表现为肾功能障碍，包括血尿氮、肌酐和尿蛋白排泄增加，以及肾脏组织病理学变化。给予氟伐他汀可显着预防 5/6Nx 大鼠的肾功能障碍和组织学异常。此外，在 5/6Nx 大鼠中观察到的基质金属蛋白酶 (MMP) 活性（如 MMP-2）的显着抑制和 NMP 组织抑制剂（TIMP）（如 TIMP-2）的显着激活几乎被氟伐他汀完全阻止，从而显着预防肾小球 ECM 积聚。对于 ECM 积累的上游介质，5/6Nx 显着上调 CTGF mRNA 表达，但氟伐他汀治疗阻止 CTGF 上调。这些结果表明，氟伐他汀作为一种众所周知的降脂药，可能通过抑制 CTGF 介导的 ECM 积累，在预防肾病方面发挥着重要作用。因此，氟伐他汀可能是开发预防糖尿病肾病的药物方法的潜在候选者，因为它具有降脂和直接抗肾 ECM 积累的作用。 (C) 2003 Elsevier Inc. 保留所有权利。
Diabetic nephropathy is related to glomerular extracellular matrix (ECM) accumulation that leads to glomerulosclerosis. Fluvastatin as a lipid-lowering medicine significantly prevents diabetic nephropathy, probably not only through its lipid-lowering action, but also mainly through its direct suppression of glomerular ECM accumulation. To test this hypothesis, in the present study, a five-sixths nephrectomized (5/6Nx) rat model to induce a renal ECM accumulation without coexistence of hyperlipidemia was used to investigate the effect of fluvastatin on renal function, glomerular ECM accumulation and expression of connective tissue growth factor (CTGF). 5/6Nx induced a significant nephropathy in rats at 13 weeks, indicated by renal dysfunction including increases in blood urine nitrogen, creatinine and urinary protein excretion, and renal histopathological changes. Administration of fluvastatin significantly prevented the renal dysfunction and histological abnormalities in the 5/6Nx rats. Furthermore, both significant suppression of matrix metalloproteinases (MMPs) activity such as MMP-2 and significant activation of tissue inhibitors of NMP (TIMPs) such as TIMP-2 observed in the 5/6Nx rats were almost completely prevented by fluvastatin, resulting in a significant prevention of glomerular ECM accumulation. For upstream mediator of ECM accumulation, 5/6Nx significantly up-regulated CTGF mRNA expression, but fluvastatin treatment prevented CTGF up-regulation. These results suggest that fluvastatin, as one of well-known lipid-lowering agents, plays an important role in the prevention of nephropathy, likely through suppression of CTGF-mediated ECM accumulation. Therefore, fluvastatin may be a potential candidate for developing a pharmaceutical approach to the prevention of diabetic nephropathy due to its both lipid-lowering and direct anti-renal ECM accumulation actions. (C) 2003 Elsevier Inc. All rights reserved.