Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction.

We and others recently reported that long-term Rho-kinase inhibition has renoprotective effects. This study was designed to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (imidapril), a Rho-kinase inhibitor (fasudil) and a combination of them both on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Imidapril (50 mg l(-1)), fasudil (1 g l(-1)) or a combination of them both was given in drinking water to mice, and their effects were compared on renal interstitial fibrosis induced by UUO. We assessed histological findings, monocyte/macrophage infiltration, myofibroblast differentiation, oxidative stress and the expression of various mRNA in the kidney by UUO. Eleven days after UUO, wild-type kidney was characterized by increased fibrotic area, dihydroethidium (DHE)-positive area, alpha-smooth muscle actin (SMA)-positive area, F4/80-positive area and the increased expression of various mRNA. Fasudil and imidapril similarly improved fibrotic area (-23%, -15%), DHE-positive area (-13%, -11%), alpha-SMA-positive area (-22%, -15%), F4/80-positive area (-42%, -34%) and the expression of various mRNA, most of which were significant (P<0.05). The combination of imidapril and fasudil further improved fibrotic area (-52%), DHE-positive area (-26%), alpha-SMA-positive area (-33%), F4/80-positive area (-62%) and the expression of various mRNA (all P<0.05 vs. monotherapy). Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor was more effective for the prevention of renal interstitial fibrosis because of the inhibition of transforming growth factor-beta/collagen, monocyte/macrophage infiltration, myofibroblast differentiation, inflammation and the oxidative stress pathway.