| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
A growing number of studies have demonstrated that Rho kinase participates importantly in the vasomotor regulation, as well as in the pathogenesis of various diseases, including vascular hypertrophy and atherosclerosis. The aims of the current project are to clarify the role of Rho kinase in mediating the control of renal vascular tone under basal and angiotensin II-stimulated conditions in renal arterioles of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), using the isolated perfused hydronephrotic rat kidney. When administered under basal vascular tone, Y-27632 caused dose-dependent dilation of afferent arterioles in WKY and SHR. Y-27632 also reversed angiotensin II-induced afferent arteriolar vasoconstriction, with 83% reversal at 10^<-5> mol/l in WKY. In contrast, the ability of Y-27632 to inhibit the KCl-induced afferent arteriolar constriction was diminished; only 38% reversal was observed at 1-^<-5> mol/l. In SHR, Y-27632 inhibited the angiotensin II-induced a
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fferent arteriolar constriction to the degree similar to that observed in WKY. The Y-27632-induced vasodilation of KCl-constricted afferent arterioles, however, was enhanced in SHR, compared with that in WKY. We further examined the effect of fasudil, a Rho-kinase inhibitor, on the progression of renal injury in salt-loaded subtotally nephrectomized SHR (SHR-Nx). In SHR-Nx treated with fasudil (3 mg/kg/day, ip), systolic blood pressure was progressively elevated (from 151±4 to 208±8 mmHg at 8 weeks, n=8), which was not different from that in SHR-Nx without fasudil (from 149±3 to 217±14mmHg, n=8). Urinary protein excretion was markedly increased in SHR-Nx (from 21±1 to 124±16mg/day at 8 weeks), but this increase was significantly suppressed by fasudil (to 79±12mg/day at 8 weeks). Renal histological examination revealed that fasudil improved glomerular (77±5 vs. 60±5, p<0.05) and tubulointerstitial injury scores )1.7±0.3 vs. 0.8±0.2, p<0.05), with parallel amelioration of proliferating cell nuclear antigen-positive cell infiltration (glomerulus, 30±4 vs. 18±3, p<0.05; tubulointerstitium, 12±1 vs. 5±2, p<0.05). In conclusions, the present study demonstrates important roles of Rho kinase pathways in mediating the renal arteriolar tone. The contribution of Rho kinase- associated calcium sensitivity to the renal arteriolar constriction, however, differs, depending on the underlying vasoconstrictor stimuli used. Furthermore, the role of Rho/ROCK in renal vasoconstriction was altered in SHR. Finally, Rho-kinase pathway is involved in the pathogenesis of renal injury, and we suggest that the inhibition of Rho-kinase may constitute a therapeutic strategy for the treatment of renal injury. Less
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