Contribution of chymase-dependent angiotensin II formation to the progression of tubulointerstitial fibrosis in obstructed kidneys in hamsters

Yu Yan Fan, Akira Nishiyama, Yoshihide Fujisawa, Hiroyuki Kobori, Daisuke Nakano, Junji Matsuura, Naoki Hase, Hirofumi Hitomi, Hideyasu Kiyomoto, Hidenori Urata, Masakazu Kohno

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Recent studies indicate a role of chymase in the regulation of angiotensin II (AngII) formation in cardiovascular and renal tissues. We investigated a possible contribution of chymase to AngII formation and to renal fibrosis in unilateral ureteral obstruction (UUO). Eight-week-old Syrian hamsters were subjected to UUO and treated with vehicle, the specific chymase inhibitor (CI) 4-[1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1H-benzimidazol-2-ylsulfanyl] -butyric acid (50 mg/kg, twice a day, p.o.), or the selective AT 1-receptor blocker olmesartan (10 mg/kg per day, p.o.) for 14 days. UUO-induced renal interstitial fibrosis was associated with increases in renal mRNA levels of α-smooth muscle actin (SMA), type I collagen, and transforming growth factor (TGF)-β. The UUO hamsters showed markedly higher AngII contents and increased AT1-receptor mRNA level in the obstructed kidney than sham-operated ones. In contrast, angiotensin-converting enzyme (ACE) protein expression was significantly lower in UUO hamsters. In UUO hamsters, treatment with CI or olmesartan significantly decreased AngII levels in renal tissue and mRNA levels of α-SMA, type I collagen, and TGF-β and ameliorated tubulointerstitial injury. On the other hand, neither CI nor olmesartan changed systolic blood pressure, renal ACE, and AT 1-receptor protein levels. These data suggest that chymase-dependent intrarenal AngII formation contributes to the pathogenesis of interstitial fibrosis in obstructed kidneys of hamsters.

Original languageEnglish
Pages (from-to)82-90
Number of pages9
JournalJournal of Pharmacological Sciences
Volume111
Issue number1
DOIs
Publication statusPublished - 2009

Keywords

  • Angiotensin II
  • Angiotensin-converting enzyme
  • Chymase
  • Unilateral ureteral obstruction

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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