Contribution of chymase-dependent angiotensin II formation to the progression of tubulointerstitial fibrosis in obstructed kidneys in hamsters.
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 alpha-smooth muscle actin (SMA), type I collagen, and transforming growth factor (TGF)-beta. The UUO hamsters showed markedly higher AngII contents and increased AT(1)-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 alpha-SMA, type I collagen, and TGF-beta 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.
Fan
Yu-Yan
YY
Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Medical School, Japan.
Nishiyama
Akira
A
Fujisawa
Yoshihide
Y
Kobori
Hiroyuki
H
Nakano
Daisuke
D
Matsuura
Junji
J
Hase
Naoki
N
Hitomi
Hirofumi
H
Kiyomoto
Hideyasu
H
Urata
Hidenori
H
Kohno
Masakazu
M
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism; D006224:Cricetinae; D018450:Disease Progression; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D009395:Nephritis, Interstitial / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*
C544931:4-(1-(4-methylbenzo(b)thiophen-3-ylmethyl)-1H-benzimidazol-2-ylsulfanyl)butyric acid; D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D002087:Butyrates; D024042:Collagen Type I; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013876:Thiophenes; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C437965:olmesartan; D007703:Peptidyl-Dipeptidase A; D053818:Chymases