Fasudil, a Rho-kinase inhibitor, attenuates... : Journal of Hypertension (original) (raw)

Original papers: Kidney

Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats

Nishikimi, Toshioa; Akimoto, Kazumib; Wang, Xina; Mori, Yosukea; Tadokoro, Kazuyoshia; Ishikawa, Yayoia; Shimokawa, Hiroakic; Ono, Hidehikoa; Matsuoka, Hiroakia

aDepartment of Hypertension and Cardiorenal Medicine and bLaboratory of Molecular and Cellular Biology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan and cDepartment of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Higashi-Ku, Fukuoka, Japan.

Sponsorship: This work was supported in part by Scientific Research Grant-in-Aid 14570692 from the Ministry of Education, Culture, Sports, Science and Technology and by the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan.

Correspondence and requests for reprints to Toshio Nishikimi, M.D., Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. Tel: +81 282 87 2149; fax: +81 282 86 1596; e-mail: [email protected]

Received 27 February 2004 Revised 28 April 2004 Accepted 3 May 2004

See editorial commentary on page 1675

Abstract

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-kinaseα, Rho-kinaseβ, collagen I and collagen III, and transforming growth factor-beta (TGF-β) 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-β (–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.