Long-Term Administration of Rho-Kinase Inhibitor Ameliorates Renal Damage in Malignant Hypertensive Rats

Abstract

Abstract-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-␤, 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-␤, 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.

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

“…Similarly, reactive oxygen species production is increased in renal inflammation and is involved in development of hypertension (19,25,32,46,49). Moreover, a variety of inflammatory mediators, such as NF-B and Rho-kinase, is involved in renal damage in hypertension, as the inhibition of NF-B ameliorates renal damage in the double-transgenic (dTGR) rat harboring both human renin and angiotensinogen genes (29) and the long-term administration of Rho-kinase inhibitor fasudil ameliorates renal damage in a model of malignant hypertension (20). Thus the results of the present study are consistent with these previous findings and indicate that renal inflammatory changes occur during and contribute to the development of ANG II-dependent malignant hypertension in Cyp1a1-Ren2 transgenic rats.…”

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…Among the major outcomes of chronic kidney disease is the development of cardiovascular disease; conversely, cardiovascular disease induces renal damage and chronic kidney disease. Fasudil has demonstrated renoprotective action in various models of renal disease, owing to combined inhibitory effects on macrophage infiltration, cell proliferation, oxidative stress, expression of extracellular matrix genes, and urinary protein reduction (Kanda et al, 2003;Nishikimi et al, 2004;Ishikawa et al, 2006). A phase 1 study (ClinicalTrials.…”

Redox Control of Renal Function and Hypertension

“…Relatively scant data are available on the role of p40 phox in hypertension. Its expression has been demonstrated in the aorta and renal cortex (136,345). In DSS rats, increased expression of p40 phox in the kidney cortices, along with p47 phox and gp91 phox , was associated with decreased renal function and increased blood pressure.…”