Fasudil, a Rho-kinase inhibitor, reverses L-NAME exacerbated severe nephrosclerosis in spontaneously hypertensive rats.

Full Abstract

BACKGROUND: In this study, we tested the hypothesis that long-term Rho-kinase inhibition would reverse nitro-L-arginine methyl ester-exacerbated nephrosclerosis in spontaneously hypertensive rats and attempted to elucidate the mechanism involved. METHODS: Five groups (each n = 8) were studied: untreated spontaneously hypertensive rats; nitro-L-arginine methyl ester (50 mg/l in drinking water, for 3 weeks)-treated spontaneously hypertensive rats; nitro-L-arginine methyl ester with fasudil (10 mg/kg/day)-treated spontaneously hypertensive rats; nitro-L-arginine methyl ester for 3 weeks followed by fasudil for 3 weeks-treated spontaneously hypertensive rats (same doses), and nitro-L-arginine methyl ester for 3 weeks followed by untreated for 3 weeks. We examined renal function, blood pressure, histological features, oxidative stress markers, and mRNA expression in the renal cortex. RESULTS: Nitro-L-arginine methyl ester-treated spontaneously hypertensive rats had higher blood pressure, proteinuria, and serum creatinine and lower creatinine clearance, urinary NO3/NO2 ratio, and urinary cGMP excretion compared with control spontaneously hypertensive rats (all Ps < 0.05). Nitro-L-arginine methyl ester-treated spontaneously hypertensive rats also had increased free radical metabolites and abnormal morphological findings with increased nicotinamide adenine dinucleotide phosphate oxidase activity, phosphorylation of myosin phosphatase targeting subunit-1, and mRNA expression of RhoA, RhoB, RhoC, collagen I and III, transforming growth factor-beta, nicotinamide adenine dinucleotide phosphate subunit, endothelial nitric oxide synthase, plasminogen activator inhibitor, and intercellular adhesion molecule-1 in the renal cortex compared with control spontaneously hypertensive rats. Long-term co-treatment with fasudil slightly improved these indices, but most of them were not statistically significant. Late fasudil treatment significantly improved kidney function, morphological changes, and alterations of mRNA expression in the renal cortex, although late untreated controls did not show any improvement. CONCLUSION: These results suggest that Rho-kinase inhibition partly reverses hypertensive glomerulosclerosis. The renoprotective effect of the Rho-kinase inhibitor may have multiple mechanisms including inhibition of extracellular matrix production, oxidative stress, adhesion molecule production, and antifibrinolysis.

Author information

Author/s: Koshikawa, Shogo (S); Nishikimi, Toshio (T); Inaba, Chikako (C); Akimoto, Kazumi (K); Matsuoka, Hiroaki (H);

Affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of hypertension (J Hypertens), published in England. (Language: eng)

Reference: 2008-Sep; vol 26 (issue 9) : pp 1837-48

Dates: Created 2008/08/13; Completed 2008/12/19; Revised 2009/01/30;

PMID: 18698220, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; pharmacology
Animals
Collagen Type I - genetics
Collagen Type III - genetics
Drug Interactions
Enzyme Inhibitors - toxicity
Hypertension, Renal - drug therapy; metabolism; pathology
Intercellular Adhesion Molecule-1 - genetics
Kidney - drug effects; enzymology
Male
NADPH Oxidase - genetics
NG-Nitroarginine Methyl Ester - toxicity
Nephrosclerosis - drug therapy; metabolism; pathology

Nephrosclerosis - drug therapy; metabolism; pathology
Nitric Oxide Synthase Type II - genetics
Oxidative Stress - drug effects
Plasminogen Activator Inhibitor 1 - genetics
Protein Kinase Inhibitors - pharmacology
RNA, Messenger - metabolism
Rats
Rats, Inbred SHR
Superoxides - metabolism
Transforming Growth Factor beta - genetics
rho-Associated Kinases - antagonists & inhibitors
rhoA GTP-Binding Protein - genetics
rhoB GTP-Binding Protein - genetics

Associated Chemicals: Collagen Type I (0) ; Collagen Type III (0) ; Enzyme Inhibitors (0) ; Plasminogen Activator Inhibitor 1 (0) ; Protein Kinase Inhibitors (0) ; RNA, Messenger (0) ; Transforming Growth Factor beta (0) ; fasudil (103745-39-7) ; Superoxides (11062-77-4) ; Intercellular Adhesion Molecule-1 (126547-89-5) ; NG-Nitroarginine Methyl Ester (50903-99-6) ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (84477-87-2) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nos3 protein, rat (EC 1.14.13.39) ; NADPH Oxidase (EC 1.6.3.1) ; rho-Associated Kinases (EC 2.7.11.1) ; rhoA GTP-Binding Protein (EC 3.6.5.2) ; rhoB GTP-Binding Protein (EC 3.6.5.2)

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