posted on 2020-11-25, 15:23authored byYan Li, Yu Pan, Shirong Cao, Kensuke Sasaki, Yinqiu Wang, Aolei Niu, Xiaofeng Fan, Suwan Wang, Ming-Zhi Zhang, Raymond C. Harris
Renal epidermal growth factor receptor (EGFR)
signaling is activated in models of diabetic nephropathy (DN), and inhibition
of EGFR signaling pathway protects against the development of DN. We have now
determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases
in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as
well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy
substrate). Either
genetic (siEGFR) or pharmacologic (AG1478) inhibition of EGFR signaling
attenuated the decreased autophagy activity. In addition, rubicon siRNA
knockdown prevented high glucose-induced inhibition of autophagy in podocytes.
We further examined whether selective
EGFR deletion in podocytes affected the progression of DN in type II diabetes. Selective
podocyte EGFR deletion had no effect on body weight or fasting blood sugars in
either db/db mice or nos3-/-; db/db mice, a model of accelerated type II DN. However selective podocyte EGFR deletion led to relative podocyte
preservation and marked reduction in albuminuria and glomerulosclerosis,
renal proinflammatory cytokine/chemokine expression and decreased pro-fibrotic and fibrotic components in nos3-/-;
db/db mice. Podocyte EGFR deletion led to decreased podocyte
expression of rubicon, in association with increased podocyte autophagy
activity. Therefore, activation of EGFR signaling in podocytes contributes to
progression of DN at least in part by increasing rubicon expression, leading to
subsequent autophagy inhibition and podocyte injury.
Funding
These studies were supported by NIH grants, DK51265, DK95785 and DK62794 (RCH, MZZ), DK103067 and the Vanderbilt O’Brien Center (P30DK114809) (RCH, MZZ), VA Merit Award 00507969 (RCH), the Vanderbilt Center for Kidney Disease, and National Natural Science Foundation of China (no.8187030028, YP).