title: Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway.
abstract: 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.
authors.affiliation: Cattedra di Nefrologia, Dipartimento di Medicina Interna, Ospedale Maggiore S. Giovanni Battista, Corso Dogliotti 14, Torino 10126, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bussolati
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Deregibus
authors.forename: Valentina
authors.initials: V
authors.lastname: Fonsato
authors.forename: Sophie
authors.initials: S
authors.lastname: Doublier
authors.forename: Tiziana
authors.initials: T
authors.lastname: Spatola
authors.forename: Simone
authors.initials: S
authors.lastname: Procida
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Carlo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012076:Renal Agents / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012076:Renal Agents; C113267:nephrin; C099252:oxidized low density lipoprotein; C494918:AKT1 protein, human