Song Ye, Li Cai, Cai Lu
Department of Pathology, Institute of Frontier Medical Science, Jilin University, Changchun, PR China.
Exp Mol Pathol. 2004 Feb;76(1):66-75. doi: 10.1016/j.yexmp.2003.08.002.
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 MMP (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.
糖尿病肾病与肾小球细胞外基质（ECM）积聚有关，后者会导致肾小球硬化。氟伐他汀作为一种降脂药物，能显著预防糖尿病肾病，其作用可能不仅通过降脂，还主要通过直接抑制肾小球ECM积聚来实现。为验证这一假设，在本研究中，使用五分之六肾切除（5/6Nx）大鼠模型来诱导肾ECM积聚且不存在高脂血症，以研究氟伐他汀对肾功能、肾小球ECM积聚及结缔组织生长因子（CTGF）表达的影响。5/6Nx在13周时诱导大鼠出现显著的肾病，表现为肾功能障碍，包括血尿素氮、肌酐和尿蛋白排泄增加，以及肾脏组织病理学改变。给予氟伐他汀可显著预防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（MMPs）活性如MMP - 2的显著抑制以及MMP组织抑制剂（TIMPs）如TIMP - 2的显著激活，几乎都被氟伐他汀完全阻止，从而显著预防了肾小球ECM积聚。对于ECM积聚的上游介质，5/6Nx显著上调CTGF mRNA表达，但氟伐他汀治疗可阻止CTGF上调。这些结果表明，氟伐他汀作为一种知名的降脂药物，在预防肾病中发挥重要作用，可能是通过抑制CTGF介导的ECM积聚来实现。因此，由于其降脂和直接抗肾ECM积聚作用，氟伐他汀可能是开发预防糖尿病肾病药物方法的潜在候选药物。
