Abstract 1105: Fasudil, a Rho-Kinase Inhibitor, Reverses but not Prevents the L-NAME-Exacerbated Severe Nephrosclerosis in Spontaneous Hypertensive Rats (SHR)
Background: Long-term Rho-kinase inhibition attenuates progression of hypertensive glomerulosclerosis in rats. In this study, we tested the hypothesis that long-term Rho-kinase inhibition prevents or reverses L-NAME-exacerbated nephrosclerosis in SHR, and attempted to elucidate the mechanism involved.
Methods: Four groups (each n=8) were studied: untreated SHR; L-NAME (50 mg/L in drinking water, for 3 weeks) treated SHR; L-NAME with fasudil (10mg/kg/day) treated SHR; and L-NAME for 3 weeks followed by fasudil for 3 weeks treated SHR (same doses). We measured renal function, blood pressure, histological findings, humoral factors, oxidative stress, and mRNA expressions in renal cortex.
Results: L-NAME treated SHR had higher blood pressure, proteinuria, and serum creatinine and lower body weight, creatinine clearance, urinary NO3/NO2 ratio, and urinary cGMP excretion compared with control (all P=0.05). L-NAME treated SHR also had increased plasma aldosterone and free radical metabolite, and abnormal morphological findings with increased mRNA expressions of RhoB, collagen I and III, TGF-beta, p40phox, p47phox, eNOS, PAI-1, and ICAM-1 in renal cortex compared with control. Long-term cotreatment with fasudil did not significantly improve these indices. However, posttreatment with fasudil significantly improved kidney function (CCr: +40%, serum Cre: -28%, proteinuria: -78%), humoral factors (aldosterone: -67%, NO3/NO2 ratio: +613%, urinary cGMP excretion: +200%), oxidative stress (free radical metabolite: -12%, biological antioxidant potential: +10%), and morphological changes (glomerular injury score: -25%, fibrous area: -12%, ED-1 positive cells: -32%) with reduction of mRNA expressions of TGF-beta (-38%), collagen I (-50%), collagen III (-54%), p40phox (-22%), p47phox (-36%), PAI-1 (-40%), ICAM-1 (-24%) and eNOS (-120%) in renal cortex.
Conclusion: Taken together with our previous studies, the results suggest that Rho-kinase inhibition not only prevents but also reverses hypertensive glomerulosclerosis in rats. The renoprotective effects of Rho-kinase inhibitor may be mediated in part by inhibition of extracellular matrix, oxidative stress, adhesion molecule and anti-fibrinolysis under the presence of NO/cGMP system.