The Role And Mechanism Of PKCα Mediates EGFR Degradation In Podocyte Injury Of Diabetic Nephropathy

A large number of studies have shown that PKCa and EGFR were involved in the pathogenesis of diabetic nephropathy[7,9,18,21,22,29-31]. However, the mechanisms of the two molecules in podocyte injury under high glucose and their relationship are unclear. Both podocytes in high glucose stimulates injury mechanism and whether correlation the two is not clear. Our studies demonstrated that:1. The expression of PKCa was increased while EGFR was decreased in diabetic nephropathy;2. The expression of PKCa was increased EGFR was decreased in diabetic rat renal tissue lysates, sub-components of the cell membrane and lipid raft area;3. High glucose stimulation induced upregulation of PKCa, downregulation of EGFR, accompanied by the decreased podocyte specific marker synaptopodin and increased podocyte injury marker;4. High glucose stimulation induced EGFR ubiquitination in podocyte in a time-dependent manner;5. PKCa specific inhibitor prevented EGFR ubiquitination and subsequent downregulation of EGFR expression in high glucose-treated podocytes;6. PKCa inhibitor and ubiquitin El activating enzyme inhibitor attenuated EGFR endocytosis and subsequently increased the membrans EGFR abundance;7. Inhibition of lysosomal degradation pathway or proteasome degradation pathway respectively induced upregulation of EGFR and synaptopodin, and downregulation of desmin. In summary, PKCa may be involved in diabetic podocyte injury through mediated EGFR ubiquitination, endocytosis and degradation; In addition, our study firstly linked PKCa and EGFR in diabetic nephropathy.This will represent a new mechanism associated with diabetes nephropathy in glomerular and podocyte injury.