GSK3β inactivation in podocytes results in decreased phosphorylation of p70S6K accompanied by cytoskeletal rearrangements and inhibited motility

Am J Physiol Renal Physiol. 2011 May;300(5):F1152-62. doi: 10.1152/ajprenal.00373.2010. Epub 2011 Jan 12.

Abstract

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 3β (GSK3β) phosphorylation, resulting in inactivation of total GSK3β kinase activity. To investigate the cellular consequences of the inactivation of GSK3β, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line
  • Cell Movement / drug effects*
  • Cytoskeletal Proteins / antagonists & inhibitors*
  • Cytoskeletal Proteins / metabolism
  • Cytoskeleton / drug effects*
  • Cytoskeleton / enzymology
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Indoles / pharmacology
  • Lithium Chloride / pharmacology
  • Maleimides / pharmacology
  • Membrane Proteins / metabolism
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins / metabolism
  • Phosphorylation
  • Podocytes / drug effects*
  • Podocytes / enzymology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • WT1 Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CD2-associated protein
  • Cytoskeletal Proteins
  • Immunosuppressive Agents
  • Indoles
  • Maleimides
  • Membrane Proteins
  • NIN protein, human
  • Nck protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • SB 216763
  • WT1 Proteins
  • nephrin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Lithium Chloride
  • Sirolimus