Podocyte EGFR Inhibits Autophagy Through Upregulation of Rubicon in Type 2 Diabetic Nephropathy.
Yan LiYu PanShirong CaoKensuke SasakiYinqiu WangAolei NiuXiaofeng FanSuwan WangMing-Zhi ZhangRaymond C HarrisPublished in: Diabetes (2020)
Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of the 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 (small interfering [si]EGFR) 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 2 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 2 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 profibrotic 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.
Keyphrases
- high glucose
- epidermal growth factor receptor
- diabetic nephropathy
- endothelial cells
- small cell lung cancer
- tyrosine kinase
- signaling pathway
- endoplasmic reticulum stress
- cell death
- advanced non small cell lung cancer
- oxidative stress
- type diabetes
- poor prognosis
- body weight
- induced apoptosis
- mass spectrometry
- gene expression
- metabolic syndrome
- cardiovascular disease
- blood pressure
- systemic sclerosis
- copy number
- long non coding rna
- cancer therapy
- diabetic rats
- skeletal muscle
- room temperature