title: Downregulation of angiotensin type 1 receptor and nuclear factor-κB by sirtuin 1 contributes to renoprotection in unilateral ureteral obstruction.
abstract: Activation of sirtuin 1 (Sirt1) attenuates unilateral ureteral obstruction (UUO)-induced inflammation and fibrosis, suggesting that Sirt1 may prevent tubulointerstitial fibrosis. In this study, we explored changes in the expression of Sirt1 in the kidneys of UUO-treated rats and evaluated the effects of Sirt1 activation or inhibition on renal pathology and mediators of UUO pathogenesis, especially angiotensin II and nuclear factor (NF)-κB, in rats and rat renal fibroblasts. Sirt1 expression increased in the obstructed kidney but not in the contralateral kidney and was mainly detected in tubulointerstitial cells. Resveratrol, a Sirt1 activator, decreased UUO-induced inflammation and fibrosis, while sirtinol, a Sirt1 inhibitor, enhanced UUO-induced inflammation. UUO increased renal angiotensin type 1 receptor (AT1R), NF-κB, monocyte chemotactic protein 1 (MCP-1), and fibronectin expression. Resveratrol attenuated these UUO-induced changes, whereas sirtinol enhanced them, with the exception of fibronectin. In renal fibroblasts, Sirt1 overexpression reduced AT1R and NF-κB levels, while Sirt1 knockdown had the opposite effects. Sirtinol increased the levels of AT1R, NF-κB, MCP-1, and connective tissue growth factor (CTGF), while resveratrol reduced AT1R levels. Our results suggested that Sirt1 inhibited AT1R and NF-κB expression in renal fibroblasts and that these mechanisms may play roles in alleviating UUO-induced damages.
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Shao-Yu
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.|Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou City, Taiwan.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Vin-Cent
authors.initials: VC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Wei-Shiung
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Kwan-Dun
authors.initials: KD
authors.lastname: Wu