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

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, Pas, 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 PIS'-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 PIS'-K pathway, Our data suggest that the effect of CsA on podocytes may contribute to the glomerular damage and that HGF could provide protection.