Contribution of Chymase-Dependent Angiotensin II Formation to the Progression of Tubulointerstitial Fibrosis in Obstructed Kidneys in Hamsters

Journal of Pharmacological Sciences

Masakazu Kohno⁵  Akira Nishiyama⁶  Hidenori Urata⁴  Hirofumi Hitomi⁶  Daisuke Nakano⁶  Junji Matsuura¹  Hiroyuki Kobori³  Yoshihide Fujisawa²  Yu-Yan Fan⁵  Hideyasu Kiyomoto⁵  Naoki Hase¹ 

[1] Pharmacology and Safety Research Department, Teijin Institute for Biomedical Research, Teijin Pharma Ltd., Japan;Life Sciences Research Center, Kagawa University Medical School, Japan;Department of Physiology, Tulane University Health Sciences Center, USA;Department of Cardiovascular Diseases, Fukuoka University Chikushi Hospital, Japan;Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Medical School, Japan;Department of Pharmacology, Kagawa University Medical School, Japan

关键词: chymase;    angiotensin II;    angiotensin-converting enzyme;    unilateral ureteral obstruction;   

DOI  :  10.1254/jphs.09152FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(39)Cited-By(8)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 AT1-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 AT1-receptor protein levels. These data suggest that chymase-dependent intrarenal AngII formation contributes to the pathogenesis of interstitial fibrosis in obstructed kidneys of hamsters.

【 授权许可】

Unknown