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Kidney Int. 2003 Dec;64(6):2009-19.

Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats.

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1
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

Abstract

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.

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