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.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India.
Sandeep
S
Kumar
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India. Electronic address: tikoo.k@gmail.com.
Kulbhushan
K
Tikoo
D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019308:Palmitic Acid; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2; C447939:SIRT1 protein, human; D056564:Sirtuin 1
Apoptosis; Insulin resistance; Podocyte death; Protein phosphatase 2A; mTORc1