Effect of fasudil on glomerulosclerosis in dahl salt-sensitive rats

WANG Xin; Nishikimi Toshio

doi:10.3760/cma.j.issn.1673-4777.2012.12.028

Abstract：Objective To explore whether the Rho-Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil which is a specific Rho-kinase inhibitor.Methods Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) were fed a high-salt diet.Fasudil [30 mg/(kg · d)] was administered for 7 weeks to DS starting.Results After 7 weeks,untreated DS had decreased kidney function,increased proteinuria and abnormal morphological findings.The systolic blood pressure i.n 7-week-old DS rats was already higher than that in DR rats[(111 ±8) mm Hg vs (104 ±6) mm Hg,P ＜0.05],and it gradually increased and reached a maximum after around 13 weeks vs (149 ± 12) mm Hg.Chronic fasudil treatment significantly improved renal function (serum creatinine,-26％ [(3.9 ± 0.4) g/L vs (5.4 ± 0.6) g/L,P ＜ 0.05],blood urea nitrogen [(214 ± 33) g/L vs (364 ±41) g/L,P ＜ 0.05],creatinine clearance [(2.08 ±0.33) ml/min vs (1.46 ± 0.47) ml/min] and proteinuria (-24％) [(17 ± 3) mg/d vs (23 ± 1) mg/d].Longterm fasudil treatment significantly attenuated the symptoms [(92 ± 13)％ vs (4 ± 1)％,P ＜ 0.01].The subcapsular symptoms and juxtamedullary cortex symptoms were markedly improved in untreated DS rats than those in DR rats.Long term fasudil treatment caused significant amelioration of these changes,especially in the glomeruli at subcapsular level [(48 ± 3) ％ vs (4 ± 1) ％,P ＜ 0.05].Fasudil treatment also attenuated the glomerular score index at the juxtamedullary cortex [(63 ± 8) ％ vs (6 ± 2) ％,P ＜ 0.05].However,there were still significant differences in the blood pressure and aforementioned parameters between DR and fasudil-treated DS.Conclusions These results suggest that the Rho-Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis in DS.Long term inhibition of the Rho-Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis.