SUN-047 PROTECTION AFFORDED BY ANGIOTENSIN II RECEPTOR ACTIVATION AGAINST ACUTE KIDNEY INJURY IS ASSOCIATED WITH UPREGULATION OF TUBULAR AUTOPHAGY

Abstract

Autophagy reportedly plays a protective role in acute kidney injury (AKI), and there is in vitro evidence to indicate that the renin-angiotensin system is involved in regulation of autophagy. Here we examined whether activation of the angiotensin II (Ang II) receptor protects the kidney from ischemia-reperfusion (I/R) injury by upregulation of autophagy in vivo. In Study 1, male Sprague-Dawley rats were assigned into treatments with vehicle (Veh) or Ang II (200 ng/kg/min). Each drug was subcutaneously infused for 72 hrs. At the end of the infusion, kidneys were removed for the assessment of autophagosomes determined as LC3 dots by immunohistochemistry. In Study 2, rats received treatments with Veh or Ang II (n=10 for each) as Study 1 and then underwent 30-min renal artery occlusion/reperfusion or sham surgery. Blood and kidneys were collected for biochemical and histological analyses. Acute tubular necrosis (ATN) score was determined in PAS stained histology at 4, and 24 h after surgery. In Study 1, the number of autophagosomes in proximal tubular cells was larger in the Ang II group than in the Veh group (0.88 vs. 0.29 a.u.; P=0.002). In Study 2, autophagosomes were increased at 4 h after I/R in the Veh group. Blood urea nitrogen (BUN) level and ATN score were significantly lower in the Ang II group than in the Veh group at 24 h after I/R (99.2 vs. 123.3 mg/dl; P=0.004, 4.0 vs. 4.6; P=0.011, respectively). The number of autophagosomes was larger in the Ang II group than in the Veh group at baseline and 4 h after I/R (0.54 vs. 4.68; P ULK1-Ser555 phosphorylation was increased in the Ang II group at 4 h after I/R. RIP1 and RIP3 levels at baseline and after I/R were not affected by Ang II (Fig). Short term infusion of Ang II increases autophagosomes in the renal tubular cells and alleviates I/R kidney injury. The renoprotective effect of Ang II may be associated with upregulation of autophagy without suppression of necroptosis.