Abstract
In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2−/− but not in Akt1−/− mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.
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Acknowledgements
We thank L.H. Noël and the clinicians of the Renal Transplant Department of Necker hospital for patient data and sample collection. We are grateful to M.J. Birnbaum (University of Pennsylvania) and M. Hall (Basel University) for Akt and Rictor mutant mice, respectively, C. Antignac (INSERM U983) for podocin-specific antibodies and R. Montjean (INSERM U983) for the PAK1-GST fusion protein expression vector. We thank M.C. Gubler, C. Antignac, C. Sumida and S. Harvey for critical advice. This work was supported by INSERM, Université Paris Descartes, Assistance Publique–Hôpitaux de Paris (AP-HP), Agence National pour la Recherche (to F.T. and M. Pontoglio), Fondation de la Recherche Médicale (to F.T. and M. Pontoglio), Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques, Association pour l'Utilisation du rein Artificiel, Roche Laboratories, the Excellence Initiative of the German Federal and State Governments EXC 294 (to T.B.H.) and European Community's Seventh Framework Program FP7/2009 - agreement number 241955, SYSCILIA (to M. Pontoglio).
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G.C. and F.B. designed and performed the experiments, analyzed the data and wrote the paper. A.V. and C.T. also performed some experiments and analyzed the data. W.B. performed the in vitro studies. C.N., M.B. and S.B. performed the mouse experiments (breeding, surgery and morphological studies). K.G. and A.O.M. performed the electron microscopy studies. S.Z. and T.B.H. provided the RictorΔpod mice and were involved in data analysis. C.L. provided and characterized patient samples and clinical outcome data. G.F., M. Pontoglio and M. Pende were involved in data analysis and wrote the paper. F.T. provided the conceptual framework and designed the study, supervised the project and wrote the paper.
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Canaud, G., Bienaimé, F., Viau, A. et al. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med 19, 1288–1296 (2013). https://doi.org/10.1038/nm.3313
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DOI: https://doi.org/10.1038/nm.3313
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