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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Nishikimi
Toshio
T
Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University School of Medicine, Mibu, Tochigi 321-0293, Japan. nishikim@dokkyomed.ac.jp
Koshikawa
Shogo
S
Ishikawa
Yayoi
Y
Akimoto
Kazumi
K
Inaba
Chikako
C
Ishimura
Kimihiko
K
Ono
Hidehiko
H
Matsuoka
Hiroaki
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D015870:Gene Expression; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D009249:NADP / Q000378:metabolism; D009400:Nephrosclerosis / Q000188:drug therapy*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D024042:Collagen Type I; D024061:Collagen Type III; D047908:Intracellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D017673:Sodium Chloride, Dietary; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D009249:NADP; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; C049347:fasudil