Autophagy upregulates (pro)renin receptor expression via reduction of P62/SQSTM1 and activation of ERK1/2 signaling pathway in podocytes

Author:

Li Caixia1,Siragy Helmy M.1

Affiliation:

1. Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia

Abstract

Autophagy plays a major role in podocytes health and disease. P62, also known as sequestosome-1 (SQSTM1), is a marker for autophagic activity and is required for the formation and degradation of ubiquitnated protein by autophagy. Knockout of p62 enhanced extracellular signal-regulated kinases (ERK1/2) activity. (pro)renin receptor (PRR) is expressed in podocytes where it contributes to the homeostasis of these cells. The influence of autophagy on PRR expression is unknown. We hypothesized that in podocytes, upregulation of autophagic activity increases PRR expression via reduction of p62 and stimulation of ERK1/2 signaling pathway. Cultured mouse podocytes were treated with the autophagy activators, rapamycin or Earle’s balanced salt solution (EBSS), for 48 h. Both rapamycin and EBSS significantly decreased p62 protein levels, increased ERK1/2 activation by phosphorylating pTpY185/187, and increased mRNA and protein expressions of PRR. Utilizing confocal microscopy demonstrated that rapamycin and EBSS significantly decreased p62/SQSTM1 and increased PRR protein expressions. Similarly, by enhancing autophagic activity by transfection with autophagy-related 5 (ATG5) cDNA or ATG7 cDNA, results similar to those observed with rapamycin and EBSS treatments were produced. Inhibition of autophagic flux with bafilomycin A1 reversed the effects of rapamycin. ERK1/2 inhibitor U0126 significantly attenuated mRNA and protein expressions of PRR in podocytes treated with rapamycin. In conclusion, upregulation of autophagy enhanced PRR expression through reduction of p62 and stimulation of ERK1/2 activity signaling pathway.

Funder

HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology

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