GSK3 beta inactivation in podocytes results in decreased phosphorylation of p70(S6K) accompanied by cytoskeletal rearrangements and inhibited motility

George B, Vollenbroker B, Saleem MA, Huber TB, Pavenstadt H, Weide T

Abstract

George B, Vollenbroker B, Saleem MA, Huber TB, Pavenstadt H, Weide T. GSK3 beta inactivation in podocytes results in decreased phosphorylation of p70(S6K) accompanied by cytoskeletal rearrangements and inhibited motility. Am J Physiol Renal Physiol 300: F1152-F1162, 2011. First published January 12, 2011; doi:10.1152/ajprenal.00373.2010.-The inhibition of mTOR kinase after renal transplantation has been associated with podocyte injury and proteinuria; however, the signaling pathways regulating these effects are not well understood. We found that prolonged rapamycin treatment in podocytes leads to an increase in glycogen synthase kinase 3 beta (GSK3 beta) phosphorylation, resulting in inactivation of total GSK3 beta kinase activity. To investigate the cellular consequences of the inactivation of GSK3 beta, we used two inhibitors reducing kinase activity and studied the cross talk between GSK3 function and the Akt/mammalian target of rapamycin (mTOR) pathway. Both GSK3 inhibitors reduced the phosphorylation of the mTOR downstream target, p70(S6K), indicating that GSK3 inhibition in podocytes is able to cause similar effects as treatment with rapamycin. Moreover, GSK3 inhibition was accompanied by the reduced expression of slit diaphragm-associated proteins and resulted in an altered cytoskeletal structure and reduced motility of podocytes, suggesting that GSK3 kinase can modulate Akt/mTOR-dependent signaling in podocytes.