Involvement of Tubular Mas Receptor in Lipid‐Induced Impaired Autophagy and ER Stress in the Kidney

Abstract

The local renin‐angiotensin system in the kidney plays an important role in development of obesity‐related kidney diseases. The purpose of current study was to investigate the role of Mas receptor in lipid‐induced kidney injuries. In human proximal tubular epithelial HK2 cells, saturated fatty acid palmitic acid (PA, 0.4mM) treatment induced increased LC3B and P62 protein expression and decreased LAMP1 expression, indicating an impaired autophagy flux and accumulation of autophagosome. This was associated with upregulated BIP and CHOP protein expression, two markers of endoplasmic reticulum stress (ER stress), and upregulated expression of cleaved caspase‐3, a marker of apoptosis. PA‐induced autophagosome accumulation, ER stress, and apoptosis was enhanced by Mas receptor agonists Ang (1‐7) or AVE0991, and suppressed by A779, a synthetic specific Mas inhibitor. PA‐induced impaired autophagy flux, increased ER stress and apoptosis were markedly attenuated by Mas receptor gene knockout in HK2 cells. Knockout Mas receptor also improved HK2 cell vitality and proliferation in response to PA treatment. Moreover, PA treatment caused elevated intracellular calcium levels, mitochondrial depolarization which were also markedly prevented by Mas knockout. Mas receptor gene knockout in HK2 cells was associated with markedly improved mitophagy after PA treatment. In mice with high‐fat diet for 12 weeks, Ang (1‐7) treatment caused enhanced autophagosome accumulation, ER stress, and apoptosis in the kidney cortex. In conclusion, Mas receptor mediated lipid‐induced impaired autophagy and ER stress in the kidney, likely contributing to tubular injuries seen in obesity‐related kidney diseases.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.