Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling
Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling
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DOI：
10.1681/asn.2005050571
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发表时间：
2006-03-01
影响因子：
13.6
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Shibata, Shigeru;Nagase, Miki;Fujita, Toshiro
据报道，他汀类药物通过多效性作用在几种肾脏疾病实验模型中提供肾脏保护。他汀类药物在肾小球足细胞中的作用尚未研究。本研究的目的是评价氟伐他汀对嘌呤霉素氨基糖苷（PAN）诱导的肾病足细胞和肾小管间质损伤的影响。PAN诱导的大量蛋白尿和血清肌酐升高在第7天，这是显着抑制氟伐他汀。足细胞相关蛋白nephrin和podocin的免疫荧光研究显示PAN肾病大鼠的染色模式减少和不连续，表明足细胞严重损伤。氟伐他汀治疗显著减轻了异常染色特征。定量分析证实PAN可降低nephrin表达，氟伐他汀可逆转nephrin表达。通过电子显微镜观察，氟伐他汀治疗的大鼠足突消失得到改善。氟伐他汀还减轻PAN肾病中的肾小管间质损伤，抑制PAN诱导的NF-κ B和肾脏中的激活蛋白-1活化。此外，PAN肾病肾小球中活化的膜结合小G T β RhoA的表达显著增加，氟伐他汀治疗可抑制该表达。在培养的足细胞中，氟伐他汀抑制PAN诱发的RhoA和肌动蛋白细胞骨架重组的激活。此外，法舒地尔，一个特定的Rho激酶抑制剂，成功地改善PAN诱导的足细胞损伤和蛋白尿。总之，氟伐他汀减轻PAN肾病足细胞和肾小管间质损伤。氟伐他汀对足细胞的有益作用可归因于对过度RhoA活性的直接调节。我们的数据表明，他汀类药物在与足细胞损伤相关的临床疾病中具有治疗作用。
Statins have been reported to confer renoprotection in several experimental models of renal disease through pleiotropic actions. The roles of statins in glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of fluvastatin on podocyte and tubulointerstitial injury in puromycin aminonucleoside (PAN)-induced nephrosis. PAN induced massive proteinuria and serum creatinine elevation on day 7, which were significantly suppressed by fluvastatin. Immunofluorescence studies of podocyte-associated proteins nephrin and podocin revealed diminished and discontinuous staining patterns in rats with PAN nephrosis, indicating severe podocyte injury. Fluvastatin treatment dramatically mitigated the abnormal staining profiles. Reduction of nephrin expression by PAN and its reversal by fluvastatin were confirmed by quantitative analyses. By electron microscopy, effacement of foot processes was ameliorated in fluvastatin-treated rats. Fluvastatin also mitigated tubulointerstitial damage in PAN nephrosis, with the repression of PAN-induced NF-kappa B and activator protein-1 activation in the kidneys. In addition, expression of activated membrane-bound small GTPase RhoA was markedly increased in the glomeruli of PAN nephrosis, which was inhibited by fluvastatin treatment. In cultured podocytes, fluvastatin suppressed PAN-evoked activation of RhoA and actin cytoskeletal reorganization. Furthermore, fasudil, a specific Rho-kinase inhibitor, successfully ameliorated PAN-induced podocyte damage and proteinuria. In summary, fluvastatin alleviated podocyte and tubulointerstitial injury in PAN nephrosis. The beneficial effects of fluvastatin on podocytes can be attributable to direct modulation of excessive RhoA activity. Our data suggest a therapeutic role for statins in clinical conditions that are relevant to podocyte injury.