Effects of exendin-4 on the intrarenal renin-angiotensin system and interstitial fibrosis in unilateral ureteral obstruction mice: Exendin-4 and unilateral ureteral obstruction.

The objective of this article is to investigate the renoprotecive effects of exendin-4 in a mouse model of unilateral ureteral obstruction (UUO) and explore the putative mechanisms. Male Balbc mice underwent sham operation or UUO surgery, and then received intraperitoneal injection of vehicle or exendin-4, respectively. After 14 days, mice were sacrificed and the left kidneys were collected and analyzed by histology, immunohistochemistry, Western blot, quantitative real-time reverse transcription polymerase chain reaction, radioimmunoassay and enzyme-linked immunosorbent assay. As compared to the sham group, mice that underwent UUO surgery developed more severe tubular injury and interstitial fibrosis, as well as higher expression of fibronectin (FN), collagen-1 (Col-1) and α-smooth muscle actin (α-SMA). Also, we observed higher expression of angiotensin-converting enzyme (ACE) while lower expression of angiotensin-converting enzyme 2 (ACE2), higher levels of intrarenal angiotensin II (Ang II) while lower levels of intrarenal angiotensin-(1-7), and higher expression of transforming growth factor β1 (TGF-β1) and phosphorylation of Smad3 (p-Smad3) in the obstructed kidneys. Impressively, these pathologic changes were significantly attenuated in the mice group of UUO treated with exendin-4. Our present study indicates for the first time that exendin-4 exerts renoprotective effects in an experimental model of UUO, partly through regulating the balance of the intrarenal renin-angiotensin system and then inhibiting the Ang II-mediated TGF-β1/Smad3 signaling pathway.

Le Y ，Zheng Z ，Xue J ，Cheng M ，Guan M ，Xue Y ... -  《-》

Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice.

Chung S ，Jeong JY ，Chang YK ，Choi DE ，Na KR ，Lim BJ ，Lee KW ... -  《-》

Alpha1-Antitrypsin Attenuates Renal Fibrosis by Inhibiting TGF-β1-Induced Epithelial Mesenchymal Transition.

Cho JH ，Ryu HM ，Oh EJ ，Yook JM ，Ahn JS ，Jung HY ，Choi JY ，Park SH ，Kim YL ，Kwak IS ，Kim CD ... -  《PLoS One》

Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy.

Liu Z ，Huang XR ，Chen HY ，Penninger JM ，Lan HY ... -  《-》

KS370G, a caffeamide derivative, attenuates unilateral ureteral obstruction-induced renal fibrosis by the reduction of inflammation and oxidative stress in mice.

Unilateral ureteral obstruction (UUO) is an established animal model used to study renal nephropathy. Caffeic acid phenethyl ester, a natural phenolic compound, possesses antifibrotic, anti-inflammation and anti-oxidative stress effects; however, rapid decomposition by esterases substantially decreases its bioavailability. The goal of this study was to investigate the beneficial effects of KS370G, a synthetic caffeamide derivative, on UUO-induced renal injury. Following the UUO, KS370G (10mg/kg) was administered by oral gavage once a day. Renal injury was analyzed at 14 days post-operation. Our results show that KS370G significantly attenuated collagen deposition in the obstructed kidney and inhibited UUO-induced renal fibrosis markers expression, including fibronectin, type I collagen, vimentin, and α-smooth muscle actin (α-SMA). KS370G significantly lowered the expression of renal inflammatory chemokines/adhesion molecules and monocyte cells marker (MCP-1, VCAM-1, ICAM-1 and CD11b). KS370G also reduced renal malondialdehyde levels and reversed the expression of renal antioxidant enzymes (SOD and catalase) after UUO. Furthermore, KS370G significantly inhibited UUO-induced elevated plasma AngII and TGF-β1 levels, TGF-β1 protein expression and Smad3 phosphorylation. These findings demonstrate that KS370G reduces renal obstructive nephropathy by possibly inhibiting AngII, TGF-β and Smad3 signaling pathways.

Chuang ST ，Kuo YH ，Su MJ 《-》