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AKT2 is essential to maintain podocyte viability and function during chronic kidney disease

Nature Medicine volume 19, pages 1288–1296 (2013)Cite this article

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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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Figure 1: Nephron reduction activates the Akt pathway in podocytes.
Figure 2: Akt2 deficiency accelerates the development of glomerular lesions.
Figure 3: Akt2 regulates podocyte survival and morphology.
Figure 4: Akt function in podocytes is isoform specific.
Figure 5: Akt2 is an intrinsic regulator of podocyte cytoskeleton and function.
Figure 6: Inhibition of AKT phosphorylation is associated with proteinuria in humans.

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References

  1. US Renal Data System. USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States (National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, 2010).

  2. Mahmoodi, B.K. et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet 380, 1649–1661 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hostetter, T.H. Progression of renal disease and renal hypertrophy. Annu. Rev. Physiol. 57, 263–278 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Hostetter, T.H. Hyperfiltration and glomerulosclerosis. Semin. Nephrol. 23, 194–199 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Kriz, W. & LeHir, M. Pathways to nephron loss starting from glomerular diseases—insights from animal models. Kidney Int. 67, 404–419 (2005).

    Article  PubMed  Google Scholar 

  6. Franke, T.F. Intracellular signaling by Akt: bound to be specific. Sci. Signal. 1, pe29 (2008).

    Article  PubMed  Google Scholar 

  7. Ceci, M., Ross, J. Jr. & Condorelli, G. Molecular determinants of the physiological adaptation to stress in the cardiomyocyte: a focus on AKT. J. Mol. Cell. Cardiol. 37, 905–912 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Manning, B.D. & Cantley, L.C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shankland, S.J. The podocyte's response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 69, 2131–2147 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Mundel, P. & Reiser, J. Proteinuria: an enzymatic disease of the podocyte? Kidney Int. 77, 571–580 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Zhu, J. et al. Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes. Kidney Int. 73, 556–566 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Huber, T.B. et al. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol. Cell. Biol. 23, 4917–4928 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chuang, P.Y. & He, J.C. Signaling in regulation of podocyte phenotypes. Nephron Physiol. 111, p9–p15 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Tejada, T. et al. Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death. Kidney Int. 73, 1385–1393 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Stylianou, K. et al. The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin. Nephrol. Dial. Transplant. 26, 498–508 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Laouari, D. et al. TGF-α mediates genetic susceptibility to chronic kidney disease. J. Am. Soc. Nephrol. 22, 327–335 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tschopp, O. et al. Essential role of protein kinase Bγ (PKBγ/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132, 2943–2954 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Yumura, W. et al. Age-associated changes in renal glomeruli of mice. Exp. Gerontol. 24, 237–249 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728–1731 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Garofalo, R.S. et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ. J. Clin. Invest. 112, 197–208 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shibata, S. et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat. Med. 14, 1370–1376 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Akilesh, S. et al. Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J. Clin. Invest. 121, 4127–4137 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Scott, R.P. et al. Podocyte-specific loss of Cdc42 leads to congenital nephropathy. J. Am. Soc. Nephrol. 23, 1149–1154 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Faul, C. et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat. Med. 14, 931–938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sarbassov, D.D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Feng, J., Park, J., Cron, P., Hess, D. & Hemmings, B.A. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J. Biol. Chem. 279, 41189–41196 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Gödel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kreis, H. et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J. Am. Soc. Nephrol. 15, 809–817 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Letavernier, E., Pe'raldi, M.N., Pariente, A., Morelon, E. & Legendre, C. Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation 80, 1198–1203 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Niranjan, T. et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat. Med. 14, 290–298 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Wei, C. et al. Modification of kidney barrier function by the urokinase receptor. Nat. Med. 14, 55–63 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Reiser, J. et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J. Clin. Invest. 113, 1390–1397 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dai, C. et al. Wnt/β-catenin signaling promotes podocyte dysfunction and albuminuria. J. Am. Soc. Nephrol. 20, 1997–2008 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ma, H. et al. Inhibition of podocyte FAK protects against proteinuria and foot process effacement. J. Am. Soc. Nephrol. 21, 1145–1156 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Faour, W.H., Thibodeau, J.F. & Kennedy, C.R. Mechanical stretch and prostaglandin E2 modulate critical signaling pathways in mouse podocytes. Cell. Signal. 22, 1222–1230 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Faul, C., Asanuma, K., Yanagida-Asanuma, E., Kim, K. & Mundel, P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 17, 428–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Reiser, J. et al. Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and α3 integrin. J. Biol. Chem. 279, 34827–34832 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Yanagida-Asanuma, E. et al. Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. Am. J. Pathol. 171, 415–427 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou, G.L. et al. Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J. Biol. Chem. 281, 36443–36453 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Welsh, G.I. et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 12, 329–340 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Letavernier, E. et al. Sirolimus interacts with pathways essential for podocyte integrity. Nephrol. Dial. Transplant. 24, 630–638 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Sarbassov, D.D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Vollenbröker, B. et al. mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes. Am. J. Physiol. Renal Physiol. 296, F418–F426 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Lamming, D.W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Inoki, K. et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest. 121, 2181–2196 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rangan, G.K. & Coombes, J.D. Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis. Nephrol. Dial. Transplant. 22, 2175–2182 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Bonegio, R.G. et al. Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy. J. Am. Soc. Nephrol. 16, 2063–2072 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Naumovic, R. et al. Effects of rapamycin on active Heymann nephritis. Am. J. Nephrol. 27, 379–389 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Ito, N. et al. mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome. Lab. Invest. 91, 1584–1595 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Diekmann, F. et al. Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass. J. Am. Soc. Nephrol. 18, 2653–2660 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Lindsley, C.W., Barnett, S.F., Layton, M.E. & Bilodeau, M.T. The PI3K/Akt pathway: recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Curr. Cancer Drug Targets 8, 7–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Cho, H., Thorvaldsen, J.L., Chu, Q., Feng, F. & Birnbaum, M.J. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349–38352 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Lu, M. et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat. Med. 18, 388–395 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Moeller, M.J., Sanden, S.K., Soofi, A., Wiggins, R.C. & Holzman, L.B. Podocyte-specific expression of cre recombinase in transgenic mice. Genesis 35, 39–42 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Terzi, F. et al. Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury. J. Clin. Invest. 106, 225–234 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shankland, S.J., Pippin, J.W., Reiser, J. & Mundel, P. Podocytes in culture: past, present, and future. Kidney Int. 72, 26–36 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Pillebout, E. et al. Proliferation and remodeling of the peritubular microcirculation after nephron reduction: association with the progression of renal lesions. Am. J. Pathol. 159, 547–560 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Viau, A. et al. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J. Clin. Invest. 120, 4065–4076 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Solez, K. et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am. J. Transplant. 8, 753–760 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Mollet, G. et al. Podocin inactivation in mature kidneys causes focal segmental glomerulosclerosis and nephrotic syndrome. J. Am. Soc. Nephrol. 20, 2181–2189 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lautrette, A. et al. Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach. Nat. Med. 11, 867–874 (2005).

    Article  CAS  PubMed  Google Scholar 

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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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Author notes

  1. Guillaume Canaud and Frank Bienaimé: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U845, Centre de Recherche 'Croissance et Signalisation', Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker–Enfants Malades, Paris, France

    Guillaume Canaud, Frank Bienaimé, Amandine Viau, Caroline Treins, William Baron, Clément Nguyen, Martine Burtin, Sophie Berissi, Gérard Friedlander, Christophe Legendre, Mario Pende & Fabiola Terzi

  2. Service de Néphrologie Transplantation Adultes, Hôpital Necker–Enfants Malades, Paris, France

    Guillaume Canaud & Christophe Legendre

  3. Service de Physiologie–Explorations Fonctionnelles, Hôpital Necker–Enfants Malades, Paris, France

    Frank Bienaimé & Gérard Friedlander

  4. Department of Radiology, Oncology and Pathology, Sapienza University, Rome, Italy

    Konstantinos Giannakakis

  5. Department of Pathology, Campus Bio-Medico University, Rome, Italy

    Andrea Onetti Muda

  6. Renal Division, University Hospital Freiburg, Freiburg, Germany

    Stefan Zschiedrich & Tobias B Huber

  7. BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany

    Stefan Zschiedrich & Tobias B Huber

  8. INSERM U1016, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8104, Université Paris Descartes, Institut Cochin, Paris, France

    Marco Pontoglio

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  1. Guillaume Canaud
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Contributions

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.

Corresponding author

Correspondence to Fabiola Terzi.

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The authors declare no competing financial interests.

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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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