Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats.
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 p27kip1, a cyclin-dependent kinase inhibitor, and increased the p27kip1 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 Rho-kinase may constitute a therapeutic strategy for the treatment of renal injury in part through the p27kip1 up-regulation and the subsequent inhibition of cell proliferation and macrophage recruitment.[1]References
- Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats. Kanda, T., Wakino, S., Hayashi, K., Homma, K., Ozawa, Y., Saruta, T. Kidney Int. (2003) [Pubmed]
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