Hormones – Cytokines – Signaling
Kidney International (2003) 64, 2009–2019; doi:10.1046/j.1523-1755.2003.00300.x
Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats
TAKESHI KANDA, SHU WAKINO, KOICHI HAYASHI, KOICHIRO HOMMA, YURI OZAWA and TAKAO SARUTA
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
Correspondence: Takao Saruta, M.D., Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail:saruta@sc.itc.keio.ac.jp
Received 4 April 2003; Revised 20 June 2003; Accepted 11 July 2003.
Abstract
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.
Keywords:
Rho-kinase, fasudil, renal injury, cell cycle, p27kip1
