Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats
Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats
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DOI：
10.1046/j.1523-1755.2003.00300.x
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发表时间：
2003-12-01
影响因子：
19.6
通讯作者：
Saruta, T
中科院分区：
文献类型：
--
作者：
Kanda, T;Wakino, S;Saruta, T
背景资料。尽管Rho-Kinase被报道在血管损伤中起重要作用，但Rho-Kinase在肾损伤进展中的作用尚不明确。我们观察了Rho激酶抑制剂法舒地尔对肾大部切除自发性高血压大鼠(SHR)肾脏损伤进展的影响。将大鼠随机分为3组：假手术组、盐负荷肾大部切除组(SHR-肾大部切除术)、SHR-肾大部切除+法舒地尔治疗6周组(SHR-肾大部切除+法舒地尔，3 mg/kg/d)。肾组织形态和分子分析及尿蛋白排泄量。SHR肾大部切除加法舒地尔治疗后的收缩压与未加法舒地尔的SHR肾大部切除组无显著差异(208+/-8 mm Hgvs 217+/-14 mm Hg)。SHR肾大部切除组尿蛋白排泄量显著增加(124+/-16 mg/d)，法舒地尔(79+/-12 mg/d)可显著抑制这一增加。肾组织学检查显示，法舒地尔改善了肾小球和肾小管间质的损伤评分，同时也改善了增殖细胞核抗原阳性和ED-1阳性的细胞浸润。此外，Western印迹分析显示，与未切除肾相比，SHR肾大部切除术后Rho-Kinase的表达和活性均增强，而法舒地尔则抑制Rho-Kinase的活性。免疫组织化学结果显示，法舒地尔上调细胞周期蛋白依赖性激酶抑制因子p27(Kip1)的表达，增加肾小球和肾小管间质中p27(Kip1)的免疫阳性细胞数。Rho-Kinase通路参与了肾损伤的发病机制。此外，抑制Rhokinase可能部分通过上调p27(Kip1)以及随后抑制细胞增殖和巨噬细胞募集而构成治疗肾损伤的策略。
Background. Although Rho-kinase is reported to play an important role in vascular injury, the contribution of Rho-kinase to the progression of renal injury remains unestablished.Methods. We examined the effect of fasudil, a Rho-kinase inhibitor, on the progression of renal injury in subtotally nephrectomized spontaneously hypertensive rats (SHR). Rats were randomly assigned to three groups: sham-operated SHR; salt-loaded subtotally nephrectomized rats(SHR-subtotal nephrectomy); SHR-subtotal nephrectomy given fasudil for 6 weeks (SHR-subtotal nephrectomy + fasudil; 3 mg/kg/day). Renal morphologic and molecular analysis as well as urinary protein excretion was evaluated.Results. In SHR-subtotal nephrectomy treated with fasudil, systolic blood pressure was not significantly different from that in SHR-subtotal nephrectomy without fasudil (208+/-8 mm Hg vs. 217+/-14 mm Hg). Urinary protein excretion was markedly increased in SHR-subtotal nephrectomy (124+/-16 mg/day), but this increase was significantly suppressed by fasudil (79+/-12 mg/day). Renal histologic examination revealed that fasudil improved glomerular and tubulointerstitial injury scores with parallel amelioration of proliferating cell nuclear antigen-positive and ED-1-positive cell infiltration. Furthermore, Western blot analyses showed that both expression and activity of Rho-kinase were enhanced in SHR-subtotal nephrectomy, compared with those in SHR without nephrectomy, and fasudil suppressed Rho-kinase activity. Finally, fasudil up-regulated the expression of p27(kip1), a cyclin-dependent kinase inhibitor, and increased the p27(kip1) immunopositive cells in both glomeruli and tubulointerstitium with the use of immunohistochemistry.Conclusion. Rho-kinase pathway is involved in the pathogenesis of renal injury. Furthermore, the inhibition of Rhokinase may constitute a therapeutic strategy for the treatment of renal injury in part through the p27(kip1) up-regulation and the subsequent inhibition of cell proliferation and macrophage recruitment.