Inhibition of Rho-kinase attenuates nephrosclerosis and improves survival in salt-loaded spontaneously hypertensive stroke-prone rats

Authors:
  • SKShogo Koshikawa
    Shogo Koshikawa
  • YIYayoi Ishikawa
    Yayoi Ishikawa
  • KAKazumi Akimoto
    Kazumi Akimoto
  • CIChikako Inaba
    Chikako Inaba
  • KIKimihiko Ishimura
    Kimihiko Ishimura
  • HOHidehiko Ono
    Hidehiko Ono
  • HMHiroaki Matsuoka
    Hiroaki Matsuoka
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Abstract
We examined whether the Rho/Rho-kinase pathway is involved in the pathogenesis of nephrosclerosis in severely hypertensive rats and assessed the effects of long-term treatment with a Rho-kinase inhibitor, fasudil, on kidney function, histological findings, gene expressions, and survival. We also attempted to elucidate the mechanisms involved. We studied the following four groups: control Wistar–Kyoto rats (WKY), untreated salt-loaded spontaneously hypertensive stroke-prone rats (SHR-SP), low-dose fasudil (15 mg/kg per day)-treated SHR-SP, and high-dose fasudil (30 mg/kg per day)-treated SHR-SP. After 8 weeks' treatment, the effects of fasudil were examined. Untreated SHR-SP were characterized by increased blood pressure without circadian variation, decreased kidney function, abnormal renal morphological findings, and increased messenger RNA expression levels of transforming growth factor beta, collagen I, collagen III, p40phox, p47phox, plasminogen activator inhibitor 1, and intracellular adhesion molecule 1 in the renal cortex, compared with WKY. Long-term high-dose fasudil treatment significantly improved renal function (serum creatinine −32%, creatine clearance +39%), proteinuria (−92%) and histological findings (glomerular injury score −57%, arteriolar injury score −55%, fibrous area −40%, ED-1-positive cells −43%) without changing blood pressure or circadian variation, compared with untreated SHR-SP. In addition, fasudil significantly improved increased mRNA expression levels in the renal cortex. Furthermore, high-dose fasudil significantly prolonged survival time compared with untreated SHR-SP (P < 0.01). Low-dose fasudil treatment improved these variables slightly, but did not affect most significantly. The Rho/Rho-kinase pathway participates in the pathogenesis of nephrosclerosis in SHR-SP independently of blood pressure-lowering activity, partly by upregulation of the gene expressions of extracellular matrix, oxidative stress, adhesion molecules, and antifibrinolysis.

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