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

Toshio Nishikimi, Kazumi Akimoto, Xin Wang, Yosuke Mori, Kazuyoshi Tadokoro, Yayoi Ishikawa, Hiroaki Shimokawa, Hidehiko Ono, Hiroaki Matsuoka

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1787-1796
Number of pages10
JournalJournal of hypertension
Volume22
Issue number9
DOIs
Publication statusPublished - 2004 Sep

Keywords

  • Fasudil
  • Hypertension-experimental
  • Nephrosclerosis
  • Rho-kinase
  • Transforming growth factors

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Fasudil, a Rho-kinase inhibitor, attenuates glomeruloscleros in Dahl salt-sensitive rats'. Together they form a unique fingerprint.

Cite this