Journal Article

The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin

Kostas Stylianou, Ioannis Petrakis, Vasiliki Mavroeidi, Stavros Stratakis, Eleftheria Vardaki, Kostas Perakis, Spyros Stratigis, Andreas Passam, Eva Papadogiorgaki, Kostas Giannakakis, Lydia Nakopoulou and Eugene Daphnis

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 26, issue 2, pages 498-508
Published in print February 2011 | ISSN: 0931-0509
Published online August 2010 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfq496
The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin

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Background. The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, has been shown to inhibit the progression of murine lupus nephritis by virtue of its potent immunosuppressive properties. The phosphoinositol-3-kinase (PI3K)/Akt pathway is a major upstream activator of mTOR and has been implicated in the propagation of cancer and autoimmunity. However, the activation status of the PI3K/Akt/mTOR pathway in lupus nephritis has not been studied so far.

Methods. In NZBW/F1 female mice, we examined the glomerular expression of Akt and mTOR by immunofluorescence and western blot. We also searched for specific phosphorylations of these kinases known to ensue during activation of the PI3K/Akt/mTOR pathway. In parallel, we examined the therapeutic role of rapamycin either before or after the development of overt lupus nephritis.

Results. We found that in untreated mice, as opposed to healthy controls, Akt and mTOR were over-expressed and phosphorylated at key activating residues. Rapamycin prolonged survival, maintained normal renal function, normalized proteinuria, restored nephrin and podocin levels, reduced anti-dsDNA titres, ameliorated histological lesions, and reduced Akt and mTOR glomerular expression activation.

Conclusions. These results suggest that: (i) the PI3K/Akt/mTOR pathway is upregulated in murine lupus nephritis, thus justifying treatment with rapamycin; (ii) rapamycin not only blocks mTOR but also negatively regulates the PI3K/Akt/mTOR pathway; and (iii) rapamycin is an effective treatment of murine lupus nephritis. Examination of the PI3K/Akt/mTOR pathway may offer new insights into the pathogenesis of lupus nephritis in humans and may lead to more individualized and less toxic treatment.

Keywords: Akt; lupus nephritis; mTOR; rapamycin

Journal Article.  5716 words.  Illustrated.

Subjects: Nephrology

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