Independent role of PP2A and mTORc1 in palmitate induced podocyte death

Molecular mechanism behind palmitate associated insulin resistance (IR) and podocyte death is not yet fully understood. The present study shows that palmitate treatment induces IR, in human urine derived podocyte-like epithelial cells (HUPECs), which is characterised by decrease in insulin-induced p-AKT, p-GSK3 β and p-ERK1/2. This impairment in insulin signalling prevents insulin induced SIRT 1 expression and deacetylation of p53. Further, palmitate treatment prevents insulin induced phosphorylation of PP2A and FOXO1 but it potentiates the phosphorylation of mTOR at Ser 2448. Interestingly, selective inhibition of PP2A, by Okadaic acid at 5 nM, restored insulin induced phosphorylation of AKT, FOXO1, SIRT1 activity and p53 degradation. However, PP2A inhibition had no effect on mTOR phosphorylation at Ser 2448. On the other hand, partial inhibition of mTORc1, by low dose of Rapamycin (1 nM) also restored phosphorylation of AKT and SIRT1 activity, whereas no significant changes were observed in insulin induced phosphorylation of PP2A after mTORc1 inhibition. To the best of our knowledge this is the first report suggesting independent role of PP2A and mTORc1 in palmitate induced IR and associated podocyte death. Therefore, the best therapeutic approach for treatment of diabetic kidney disease should involve manipulating phosphorylation of both PP2A and mTORc1.