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

OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSION 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.