Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats.
OBJECTIVE: The present study was designed to clarify whether the Rho- Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil, a specific Rho-kinase inhibitor. METHOD AND RESULTS: Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) were fed a high-salt diet at 6 weeks of age. Fasudil (30 mg/kg per day) was administered for 7 weeks to DS starting at the age of 11 weeks. After 7 weeks, untreated DS were characterized by decreased kidney function, increased proteinuria, abnormal morphological findings, increased adrenomedullin and atrial natriuretic peptide ( ANP) levels, and increased renal messenger RNA expression of RhoB, Rho-kinasealpha, Rho-kinasebeta, collagen I and collagen III, and transforming growth factor-beta (TGF-beta) in the renal cortex compared with DR. Chronic fasudil treatment significantly improved renal function (serum creatinine, -26%; blood urea nitrogen, -41%; creatinine clearance, +42%), proteinuria (-24%) and histological findings (glomerular injury score, -49%; afferent arteriolar injury score, -17%) without changing blood pressure compared with untreated DS. Interestingly, long-term fasudil treatment decreased the plasma adrenomedullin (-25%) and ANP (-49%), but did not change the plasma renin or aldosterone. Furthermore, fasudil significantly decreased the messenger RNA expression of TGF-beta (-20%), collagen I (-23%), and collagen III (-24%) in the renal cortex. However, there were still significant differences in the aforementioned parameters between DR and fasudil-treated DS. CONCLUSION: These results suggest that the Rho- Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis independently of blood pressure in DS, and that chronic inhibition of the Rho- Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis.[1]References
- Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats. Nishikimi, T., Akimoto, K., Wang, X., Mori, Y., Tadokoro, K., Ishikawa, Y., Shimokawa, H., Ono, H., Matsuoka, H. J. Hypertens. (2004) [Pubmed]
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