Abstract 5075: Beneficial Effects of Combination of ACE Inhibitor and Rho-kinase Inhibitor on Tubulointerstitial Fibrosis Induced by Unilateral Ureteral Obstruction
Objects: We recently reported that long-term Rho-kinase inhibition attenuates glomerulosclerosis in severe hypertension, salt-induced hypertension, and malignant hypertension rat model. In addition, ACE inhibitor is well known to prevent renal fibrosis. This study was design to compare the effects of ACE inhibitor (imidapril), Rho-kinase inhibitor (fasudil), and their combination on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved.
Methods: Imidapril (50mg/L), fasudil (1g/L), or their combination was given in drinking water to mouse (C57BL/6, each group: n =8), and their effects were compared on renal interstitial fibrosis induced by UUO. We measured histological findings, immunohistological findings, oxidative stress, and various mRNA expressions in the kidney by UUO.
Results: Eleven days after UUO, wild type kidney was characterized increased fibrotic area (Masson’s trichrome stain positive area), dihydroethidium (DHE) positive area, α-SMA positive area, F4/80 positive area, and increased various mRNA expressions. Fasudil and imidapril similarly improved fibrotic area (−23%, −15%), DHE positive area (−13%, −11%), α-SMA positive area (−22%, −15%), F4/80 positive area (−42%, −34%), and various mRNA expressions (TGF-β: −20%, −18%; CollagenI: −37%, −19%; CollagenIII: −36%, −26%; MCP-1: −22%, −34%, TNF-α: −7%, −13%), most of which were significant (P< 0.05). Combination of imidapril and fasudil further improved fibrotic area (−52%), DHE positive area (−26%), α-SMA positive area (−33%), F4/80 positive area (−62%), and various mRNA expressions (TGF-β:−48%; CollagenI:−65%; CollagenIII:−59%; MCP-1:−54%, TNF-α: −33%) (all P <0.05 vs monotherapy).
Conclusion: Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor is more effective in the prevention of renal interstitial fibrosis due to inhibition of TGF-β/collagen, migration of monocyte/macrophage, differentiation of fibroblast, inflammation, and oxidative stress pathway. Combination of an ACE inhibitor and a Rho-kinase inhibitor may be a possible new therapeutic strategy for chronic kidney disease.