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.
Takeda
Yosuke
Y
Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan.
Nishikimi
Toshio
T
Akimoto
Kazumi
K
Matsuoka
Hiroaki
H
Ishimitsu
Toshihiko
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000199:Actins / Q000032:analysis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D004359:Drug Therapy, Combination; D004996:Ethidium / Q000031:analogs & derivatives / Q000032:analysis; D048289:Imidazolidines / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D014517:Ureteral Obstruction / Q000150:complications; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D000943:Antigens, Differentiation; D048289:Imidazolidines; C544013:alpha-smooth muscle actin, mouse; C036763:monocyte-macrophage differentiation antigen; C067883:dihydroethidium; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C065166:imidapril; D054460:rho-Associated Kinases; D004996:Ethidium; C049347:fasudil