Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway

被引：110

作者：

Bussolati, B

Deregibus, MC

Fonsato, V

Doublier, S

Spatola, T

Procida, S

Di Carlo, F

Camussi, G

机构：

[1] Osped Maggiore S Giovanni Battista, Dipartimento Med Interna, Cattedra Nefrol, Ctr Ric Med Sperimentale, I-10126 Turin, Italy

[2] Univ Turin, Dipartimento Sci Clin & Biol, Turin, Italy

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2005年 / 16卷 / 07期

关键词：

D O I：

10.1681/ASN.2004080629

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1936 / 1947

页数：12

共 45 条

[1]

Barisoni L., Mundel P., Podocyte biology and the emerging understanding of podocyte diseases, Am J Nephrol, 23, pp. 353-360, (2003)

[2]

Tryggvason K., Wartiovaara J., Molecular basis of glomerular permselectivity, Curr Opin Nephrol Hypertens, 10, pp. 543-549, (2001)

[3]

Kestila M., Lenkkeri U., Mannikko M., Lamerdin J., McCready P., Putaala H., Ruotsalainen V., Morita T., Nissinen M., Herva R., Kashtan C.E., Peltonen L., Holmberg C., Olsen A., Tryggvason K., Positionally cloned gene for a novel glomerular protein-nephrin-is mutated in congenital nephrotic syndrome, Mol Cell, 1, pp. 575-582, (1998)

[4]

Lenkkeri U., Mannikko M., McCready P., Lamerdin J., Gribouval O., Niaudet P.M., Antignac C.K., Kashtan C.E., Homberg C., Olsen A., Kestila M., Tryggvason K., Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations, Am J Hum Genet, 64, pp. 51-61, (1999)

[5]

Luimula P., Ahola H., Wang S.X., Solin M.L., Aaltonen P., Tikkanen I., Kerjaschki D., Holthofer H., Nephrin in experimental glomerular disease, Kidney Int, 58, pp. 1461-1468, (2000)

[6]

Salant D.J., Topham P.S., Role of nephrin in proteinuric renal diseases, Springer Semin Immunopathol, 24, pp. 423-439, (2003)

[7]

Furness P.N., Hall L.L., Shaw J.A., Pringle J.H., Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome, Nephrol Dial Transplant, 14, pp. 1234-1237, (1999)

[8]

Doublier S., Ruotsalainen V., Salvidio G., Lupia E., Biancone L., Conaldi P.G., Reponen P., Tryggvason K., Camussi G., Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome, Am J Pathol, 158, pp. 1723-1731, (2001)

[9]

Huh W., Kim D.J., Kim M.K., Kim Y.G., Oh H.Y., Ruotsalainen V., Tryggvason K., Expression of nephrin in acquired human glomerular disease, Nephrol Dial Transplant, 17, pp. 478-484, (2002)

[10]

Wanner C., Greiber S., Kramer-Guth A., Heinloth A., Galle J., Lipids and progression of renal disease: Role of modified low density lipoprotein and lipoprotein(a), Kidney Int, 63, (1997)

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