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Statins Prevent Oxidized LDL-Induced Injury of Glomerular Podocytes by Activating the Phosphatidylinositol 3-Kinase/AKT-Signaling Pathway

Benedetta Bussolati^*,, Maria Chiara Deregibus^*, Valentina Fonsato^*, Sophie Doublier^*, Tiziana Spatola^*, Simone Procida^*, Francesco Di Carlo and Giovanni Camussi^*

^* Cattedra di Nefrologia, Dipartimento di Medicina Interna, Centro Ricerca Medicina Sperimentale, and Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Torino, Italy

Address correspondence to: Dr. Giovanni Camussi, Cattedra di Nefrologia, Dipartimento di Medicina Interna, Ospedale Maggiore S. Giovanni Battista, Corso Dogliotti 14, Torino 10126, Italy. Phone: 39-011-6336708; Fax: 39-011-6631184; E-mail: giovanni.camussi{at}unito.it

Received for publication August 2, 2004. Accepted for publication March 7, 2005.

The injury of podocytes is associated with alterations of the glomerular size-selective barrier to proteins. In this study, oxidized LDL (oxLDL) but not native LDL induced apoptosis in human cultured podocytes and reduced Akt activity and P-Akt/Akt ratio. Moreover, oxLDL-induced redistribution and loss of nephrin, an adhesion molecule specific for the glomerular slit diaphragm. Nephrin reduction was preceded by inhibition of nephrin tyrosine phosphorylation and of its association with p85 phosphatidylinositol 3-kinase (PI3K). Moreover, three different statins, mevastatin, pravastatin, and simvastatin, inhibited in a dose-dependent manner apoptosis and loss of nephrin induced by oxLDL by stimulating Akt activity. In addition, simvastatin significantly increased the expression of nephrin protein and mRNA by podocytes. The protective effects of statins were blocked by treatment of podocytes with two unrelated pharmacologic inhibitors of PI3K, LY294002 and wortmannin, suggesting a role for PI3K, and by mevalonate, indicating dependency on HMG-CoA reductase activity. Statins directly stimulated Akt phosphorylation ad activity. Finally, oxLDL induced a retraction of cultured podocytes and an increase in the albumin diffusion across their monolayer that was inhibited by treatment with statins. In conclusion, statins reduced the oxLDL-induced apoptosis and loss of nephrin in glomerular podocytes. The statin-induced Akt activation may protect from the loss of nephrin by an inhibition of its redistribution and shedding and by a stimulation of its synthesis. These data provide a rationale for the anti-proteinuric effect of statins.

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