Long-term administration of rho-kinase inhibitor ameliorates renal damage in malignant hypertensive rats.
We have shown recently that fasudil, a Rho-kinase inhibitor, has renoprotective effects in salt-sensitive hypertensive rats. We hypothesized that activation of Rho-kinase is involved in the pathogenesis of glomerulosclerosis in malignant hypertensive rats. To test this hypothesis, we studied the following 4 groups: control Wistar-Kyoto rats, untreated deoxycorticosterone-acetate salt spontaneously hypertensive rats (DOCA-SHR), low-dose fasudil-treated DOCA-SHR, and high-dose fasudil-treated DOCA-SHR. After 3 weeks of treatment, the effects of fasudil were examined. DOCA-SHR was characterized by increased blood pressure (BP); increased kidney weight; decreased renal function; increased proteinuria; abnormal histological findings; increased monocyte/macrophage infiltration; increased urinary 8-isoprostran levels; increased gene expression of collagen I, collagen III, transforming growth factor-beta, and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits (p40phox, p47phox, and p67phox); and decreased gene expression of endothelial NO synthase (eNOS) in the renal cortex as compared with Wistar-Kyoto rats. Long-term high-dose fasudil treatment significantly improved renal function and histological findings without changing BP, as compared with untreated DOCA-SHR. Interestingly, long-term fasudil treatment significantly decreased monocyte/macrophage infiltration and urinary 8-isoprostran excretion, in association with decreased mRNA levels of transforming growth factor-beta, collagen I, collagen III, and NADPH oxidase subunits (p40phox, p47phox, and p67phox), and increased mRNA levels of eNOS in the renal cortex. Long-term low-dose fasudil treatment tended to improve these variables slightly but did not affect most of them significantly. Our results suggest that long-term fasudil treatment provides renoprotective effects independent of BP-lowering activity. These renoprotective effects are associated with inhibition of extracellular matrix gene expression, monocyte/macrophage infiltration, oxidative stress, and upregulation of eNOS gene expression.
Ishikawa
Yayoi
Y
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Nishikimi
Toshio
T
Akimoto
Kazumi
K
Ishimura
Kimihiko
K
Ono
Hidehiko
H
Matsuoka
Hiroaki
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003900:Desoxycorticosterone; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D053331:Ectodysplasins; D015870:Gene Expression; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007672:Kidney Cortex / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009249:NADP / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D048069:Tumor Necrosis Factors / Q000378:metabolism; D054460:rho-Associated Kinases
D053331:Ectodysplasins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D048069:Tumor Necrosis Factors; C075750:8-epi-prostaglandin F2alpha; D003900:Desoxycorticosterone; D009249:NADP; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015237:Dinoprost; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil