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(American Journal of Pathology. 2001;158:275-280.)
© 2001 American Society for Investigative Pathology

Regular Articles

Hepatocyte Growth Factor, but Not Insulin-Like Growth Factor I, Protects Podocytes against Cyclosporin A-Induced Apoptosis

Alessia Fornoni^*, Hong Li, Annalisa Foschi, Gary E. Striker^* and Liliane J. Striker^*

From the Renal Cell Biology Laboratory^*
and the Division of Pulmonary and Critical Care Medicine,
Department of Medicine, University of Miami School of Medicine, Miami, Florida; and the Division of Nephrology and Dialysis,
IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy

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.

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