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

J Renin Angiotensin Aldosterone Syst. 2016 Dec 2;17(4):1470320316677918. doi: 10.1177/1470320316677918. Print 2016 Oct.

Abstract

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.

Keywords: Angiotensin-converting enzyme; TGF-β1/Smad3; angiotensin II; angiotensin-converting enzyme 2; exendin-4; intrarenal renin-angiotensin system; unilateral ureteral obstruction.

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Angiotensin I / metabolism
  • Angiotensin II / metabolism
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Exenatide
  • Fibronectins / genetics
  • Fibronectins / metabolism
  • Fibrosis
  • Kidney / drug effects
  • Kidney / pathology*
  • Male
  • Mice, Inbred BALB C
  • Peptide Fragments / metabolism
  • Peptides / pharmacology*
  • Peptides / therapeutic use*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Renin-Angiotensin System / drug effects*
  • Signal Transduction / drug effects
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta1 / metabolism
  • Ureteral Obstruction / drug therapy*
  • Ureteral Obstruction / genetics
  • Ureteral Obstruction / pathology*
  • Venoms / pharmacology*
  • Venoms / therapeutic use*

Substances

  • Acta2 protein, mouse
  • Actins
  • Collagen Type I
  • Fibronectins
  • Peptide Fragments
  • Peptides
  • RNA, Messenger
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • Venoms
  • Angiotensin II
  • Angiotensin I
  • Exenatide
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)