Phosphatidylinositol 3 kinase (PI 3 K) regulates glomerular mesangial cell chemotaxis and proliferation: Involvement of mitogen activated protein kinase (MAPK)-dependent and independent pathways

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Abstract

Proliferation and migration are biologic responses of mesangial cells during inflammatory glomerular disease. Both PDGF and its receptor (PDGFR) are upregulaled in the mesangium during glomerular injury. We have recently shown that PDGF stimulates PI 3 K activity in cultured mesangial cells. Using PDGFR mutants defective in PI 3 K activation, a role of this enzyme has been implicated in proliferation and chemolaxis of transfected cells overexpressing this receptor. However, the role of this enzyme in regulating chemotaxis and proliferation of primary mesangial cells has not yet been addressed. In this study, we used wortmannin (WMN), a specific inhibitor of PI 3 K. WMN dose dependency inhibited PI 3 K activity in antiphosphotyrosine and anli-PDGFR immunoprecipitates of PDGF-stimulated mesangial cell lysate. In vitro immunokinase assay of anti-Pi 3 K immunobeads showed no effect of WMN on association of this enzyme with PDGFR. Treatment of mesangial cells with different concentrations of WMN inhibited PDGF-induced chemotaxis and DNA synthesis in a dose-dependent manner. It has recently been shown that PI 3 K can physically interact with Ras protein. Since Ras is the upstream regulator of the kinase cascade leading to the activation of MAPK, we determined if stimulation of PI 3 K is necessary for activation of MAPK in mesangial cells. Using myelin basic protein as substrate, MAPK activity was measured in anti-MAPK immunoprecipitates of PDGF-stimulated mesangial cells after pretreatment with WMN. The data showed significant but not complete inhibition of PDGF-induced MAPK activity in WMN treated cells. These data indicate that PI 3 K dependent and independent signal transduction pathways are involved in the activation of MAPK in mesangial cells.

Original languageEnglish (US)
Pages (from-to)A995
JournalFASEB Journal
Volume10
Issue number6
StatePublished - Dec 1 1996

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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