Hepatocyte growth factor, but not insulin-like growth factor I, protects podocytes against cyclosporin A-induced apoptosis

Am J Pathol. 2001 Jan;158(1):275-80. doi: 10.1016/S0002-9440(10)63966-1.

Abstract

Cyclosporin A (CsA) nephropathy is associated with altered expression of apoptosis regulatory genes such as Fas-ligand and Bcl-2 family members in the glomerular, tubulointerstitial, and vascular compartments. Both hepatocyte growth factor (HGF) and insulin-like growth factor (IGF-I) protect against apoptosis, and HGF specifically up-regulates Bcl-xL, a protein that regulates apoptosis. We investigated whether Bcl-xL and Fas/Fas-ligand were regulated by CsA in cultured podocytes and whether CsA-induced apoptosis was prevented by HGF or IGF-I. A murine podocyte cell line was treated with CsA in the presence or absence of HGF or IGF-I. Apoptosis was quantitated by ELISA and by flow cytometry; Bcl-xL, Fas, and Fas-ligand were measured by Western blotting. Inhibitors of MAP kinase/ERK kinase (MEK)-1 and of phosphatidylinositol 3'-kinase (PI3'-K) were used to determine the signaling pathways involved in Bcl-xL regulation. Apoptosis was induced by CsA in a dose- and time-dependent fashion. CsA also decreased Bcl-xL levels. HGF, but not IGF-I, prevented apoptosis and restored Bcl-xL levels. The regulation of Bcl-xL by HGF was mediated by the PI3'-K but not by the MEK-1 pathway. In summary, we showed that CsA induces apoptosis in podocytes. Apoptosis was prevented by pretreatment with HGF but not IGF-I. Decreased apoptosis appeared to be mediated by regulation of Bcl-xL via the PI3'-K pathway. Our data suggest that the effect of CsA on podocytes may contribute to the glomerular damage and that HGF could provide protection.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cells, Cultured
  • Cyclosporine / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Fas Ligand Protein
  • Female
  • Flavonoids / pharmacology
  • Hepatocyte Growth Factor / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology*
  • Kidney Glomerulus / cytology
  • Kidney Glomerulus / drug effects*
  • Kidney Glomerulus / metabolism
  • MAP Kinase Kinase 1
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Time Factors
  • bcl-X Protein
  • fas Receptor / drug effects
  • fas Receptor / metabolism

Substances

  • Bcl2l1 protein, mouse
  • Enzyme Inhibitors
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Flavonoids
  • Membrane Glycoproteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • fas Receptor
  • Hepatocyte Growth Factor
  • Insulin-Like Growth Factor I
  • Cyclosporine
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one