Downregulation of angiotensin type 1 receptor and nuclear factor-κB by sirtuin 1 contributes to renoprotection in unilateral ureteral obstruction

Shao-Yu Yang; Shuei-Liong Lin; Yung-Ming Chen; Vin-Cent Wu; Wei-Shiung Yang; Kwan-Dun Wu

doi:10.1038/srep33705

Downregulation of angiotensin type 1 receptor and nuclear factor-κB by sirtuin 1 contributes to renoprotection in unilateral ureteral obstruction

Sci Rep. 2016 Sep 23:6:33705. doi: 10.1038/srep33705.

Authors

Shao-Yu Yang^{1

2}, Shuei-Liong Lin^{2

3}, Yung-Ming Chen^{2

4}, Vin-Cent Wu², Wei-Shiung Yang^{1

2}, Kwan-Dun Wu²

Affiliations

¹ Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
² Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
³ Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou City, Taiwan.

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.