Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling

Nature Medicine volume 18, pages 111–119 (2012)Cite this article

Subjects

Abstract

Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes—differentiated epithelial cells crucial for filtration—are thought to lack substantial capacity for regeneration. Here we show that podocytes rapidly lose differentiation markers and enter the cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression in mice induces marked upregulation of Wnt signaling and disrupts glomerular structure, resulting in a collapsing glomerulopathy resembling those in human disease, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased expression of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Silencing transgenic TERT expression or inhibiting Wnt signaling through systemic expression of the Wnt inhibitor Dkk1 in either TERT transgenic mice or in a mouse model of HIVAN results in marked normalization of podocytes, including rapid cell-cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected capacity of podocytes to reversibly enter the cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt–β-catenin pathways in podocyte proliferation and disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Conditional induction of TERT impairs survival and induces a collapsing glomerulopathy.
Figure 2: TERT induces podocyte dedifferentiation and proliferation.
Figure 3: TERT induces activation of the Wnt signaling pathway in podocytes.
Figure 4: β-catenin is stabilized and TERT expression is increased in human collapsing glomerulopathies and in a mouse model of HIVAN.
Figure 5: Proliferating podocytes return to a quiescent, differentiated state after doxycycline withdrawal in i-TERTci mice.
Figure 6: Acute inhibition of Wnt signaling in i-TERTci and Tg26 HIVAN mice ameliorates disease progression.

Similar content being viewed by others

References

  1. Nadasdy, T., Laszik, Z., Blick, K.E., Johnson, L.D. & Silva, F.G. Proliferative activity of intrinsic cell populations in the normal human kidney. J. Am. Soc. Nephrol. 4, 2032–2039 (1994).

    CAS  Google Scholar 

  2. Humphreys, B.D. et al. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2, 284–291 (2008).

    Article  CAS  Google Scholar 

  3. Mundel, P. & Shankland, S.J. Podocyte biology and response to injury. J. Am. Soc. Nephrol. 13, 3005–3015 (2002).

    Article  Google Scholar 

  4. Barisoni, L., Kriz, W., Mundel, P. & D'Agati, V. The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J. Am. Soc. Nephrol. 10, 51–61 (1999).

    CAS  Google Scholar 

  5. Pavenstädt, H., Kriz, W. & Kretzler, M. Cell biology of the glomerular podocyte. Physiol. Rev. 83, 253–307 (2003).

    Article  Google Scholar 

  6. Kriz, W. Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc. Res. Tech. 57, 189–195 (2002).

    Article  Google Scholar 

  7. 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  Google Scholar 

  8. Pavenstädt, H. Roles of the podocyte in glomerular function. Am. J. Physiol. Renal Physiol. 278, F173–F179 (2000).

    Article  Google Scholar 

  9. Kriz, W. Progressive renal failure–inability of podocytes to replicate and the consequences for development of glomerulosclerosis. Nephrol. Dial. Transplant. 11, 1738–1742 (1996).

    CAS  Google Scholar 

  10. Shankland, S.J. & Wolf, G. Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. Am. J. Physiol. Renal Physiol. 278, F515–F529 (2000).

    Article  CAS  Google Scholar 

  11. Barisoni, L. et al. Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies. Kidney Int. 58, 137–143 (2000).

    Article  CAS  Google Scholar 

  12. Husain, M., D'Agati, V.D., He, J.C., Klotman, M.E. & Klotman, P.E. HIV-1 Nef induces dedifferentiation of podocytes in vivo: a characteristic feature of HIVAN. AIDS 19, 1975–1980 (2005).

    Article  CAS  Google Scholar 

  13. Zuo, Y. et al. HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J. Am. Soc. Nephrol. 17, 2832–2843 (2006).

    Article  CAS  Google Scholar 

  14. Rosenstiel, P., Gharavi, A., D'Agati, V. & Klotman, P. Transgenic and infectious animal models of HIV-associated nephropathy. J. Am. Soc. Nephrol. 20, 2296–2304 (2009).

    Article  Google Scholar 

  15. Ding, M. et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat. Med. 12, 1081–1087 (2006).

    Article  CAS  Google Scholar 

  16. Korgaonkar, S.N. et al. HIV-1 upregulates VEGF in podocytes. J. Am. Soc. Nephrol. 19, 877–883 (2008).

    Article  CAS  Google Scholar 

  17. Ronconi, E. et al. Regeneration of glomerular podocytes by human renal progenitors. J. Am. Soc. Nephrol. 20, 322–332 (2009).

    Article  CAS  Google Scholar 

  18. Appel, D. et al. Recruitment of podocytes from glomerular parietal epithelial cells. J. Am. Soc. Nephrol. 20, 333–343 (2009).

    Article  CAS  Google Scholar 

  19. Lee, H.W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).

    Article  CAS  Google Scholar 

  20. Allsopp, R.C., Morin, G.B., DePinho, R., Harley, C.B. & Weissman, I.L. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102, 517–520 (2003).

    Article  CAS  Google Scholar 

  21. Batista, L.F. et al. Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474, 399–402 (2011).

    Article  CAS  Google Scholar 

  22. Sarin, K.Y. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005).

    Article  CAS  Google Scholar 

  23. Choi, J. et al. TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet. 4, e10 (2008).

    Article  Google Scholar 

  24. Park, J.I. et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460, 66–72 (2009).

    Article  CAS  Google Scholar 

  25. D'Agati, V. Pathologic classification of focal segmental glomerulosclerosis. Semin. Nephrol. 23, 117–134 (2003).

    Article  Google Scholar 

  26. Imai, E. et al. Glowing podocytes in living mouse: transgenic mouse carrying a podocyte-specific promoter. Exp. Nephrol. 7, 63–66 (1999).

    Article  CAS  Google Scholar 

  27. Kaplan, J.M. et al. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat. Genet. 24, 251–256 (2000).

    Article  CAS  Google Scholar 

  28. Marshall, C.B. & Shankland, S.J. Cell cycle regulatory proteins in podocyte health and disease. Nephron Exp. Nephrol. 106, e51–e59 (2007).

    Article  CAS  Google Scholar 

  29. Nagata, M., Nakayama, K., Terada, Y., Hoshi, S. & Watanabe, T. Cell cycle regulation and differentiation in the human podocyte lineage. Am. J. Pathol. 153, 1511–1520 (1998).

    Article  CAS  Google Scholar 

  30. Mundel, P., Reiser, J. & Kriz, W. Induction of differentiation in cultured rat and human podocytes. J. Am. Soc. Nephrol. 8, 697–705 (1997).

    CAS  Google Scholar 

  31. Mundel, P. et al. Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J. Cell Biol. 139, 193–204 (1997).

    Article  CAS  Google Scholar 

  32. Reiser, J., Kriz, W., Kretzler, M. & Mundel, P. The glomerular slit diaphragm is a modified adherens junction. J. Am. Soc. Nephrol. 11, 1–8 (2000).

    CAS  Google Scholar 

  33. Heikkilä, E. et al. Densin and β-catenin form a complex and co-localize in cultured podocyte cell junctions. Mol. Cell. Biochem. 305, 9–18 (2007).

    Article  Google Scholar 

  34. Lustig, B. et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol. Cell. Biol. 22, 1184–1193 (2002).

    Article  CAS  Google Scholar 

  35. Dickie, P. et al. HIV-associated nephropathy in transgenic mice expressing HIV-1 genes. Virology 185, 109–119 (1991).

    Article  CAS  Google Scholar 

  36. Bruggeman, L.A. et al. Renal epithelium is a previously unrecognized site of HIV-1 infection. J. Am. Soc. Nephrol. 11, 2079–2087 (2000).

    CAS  Google Scholar 

  37. Bafico, A., Liu, G., Yaniv, A., Gazit, A. & Aaronson, S.A. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat. Cell Biol. 3, 683–686 (2001).

    Article  CAS  Google Scholar 

  38. Mao, B. et al. LDL-receptor–related protein 6 is a receptor for Dickkopf proteins. Nature 411, 321–325 (2001).

    Article  CAS  Google Scholar 

  39. Semënov, M.V. et al. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr. Biol. 11, 951–961 (2001).

    Article  Google Scholar 

  40. Mao, B. et al. Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling. Nature 417, 664–667 (2002).

    Article  CAS  Google Scholar 

  41. Kuhnert, F. et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl. Acad. Sci. USA 101, 266–271 (2004).

    Article  CAS  Google Scholar 

  42. Iglesias, D.M. et al. Canonical WNT signaling during kidney development. Am. J. Physiol. Renal Physiol. 293, F494–F500 (2007).

    Article  CAS  Google Scholar 

  43. Stark, K., Vainio, S., Vassileva, G. & McMahon, A.P. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683 (1994).

    Article  CAS  Google Scholar 

  44. Carroll, T.J., Park, J.S., Hayashi, S., Majumdar, A. & McMahon, A.P. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev. Cell 9, 283–292 (2005).

    Article  CAS  Google Scholar 

  45. Lancaster, M.A. et al. Impaired Wnt–β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat. Med. 15, 1046–1054 (2009).

    Article  CAS  Google Scholar 

  46. Lin, S.L. et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc. Natl. Acad. Sci. USA 107, 4194–4199 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. He, W., Kang, Y.S., Dai, C. & Liu, Y. Blockade of Wnt/β-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury. J. Am. Soc. Nephrol. 22, 90–103 (2011).

    Article  CAS  Google Scholar 

  49. Kato, H. et al. The Wnt/β-catenin pathway in podocytes integrates cell adhesion, differentiation and survival. J. Biol. Chem. 286, 26003–26015 (2011).

    Article  CAS  Google Scholar 

  50. Sagrinati, C. et al. Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. J. Am. Soc. Nephrol. 17, 2443–2456 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Chu in the Stanford Comparative Medicine Histology Research Core Laboratory, S. Busque for guidance with nephrectomy, and R. Nusse, Stanford University, for Axin2LacZ/+ mice. M.S. was supported by the Stanford School of Medicine Dean's postdoctoral fellowship and the Stanford Center on Longevity postdoctoral fellowship. This work was supported by US National Institutes of Health grants DK085527 and DK085720 to C.J.K., DK087626 to A.G.G. and CA111691, CA125453, AG033747 and AG036695 to S.E.A.

Author information

Author notes

  1. Marina Shkreli

    Present address: Present address: Laboratory of Biology and Pathology of Genomes, University of Nice, Nice, France.,

Authors and Affiliations

  1. Department of Medicine, Stanford School of Medicine, Stanford, California, USA

    Marina Shkreli, Kavita Y Sarin, Matthew F Pech, Woody Chang, Stephanie A Brockman, Peggie Cheung, Eunice Lee, Frank Kuhnert, Calvin J Kuo & Steven E Artandi

  2. Program in Cancer Biology, Stanford School of Medicine, Stanford, California, USA

    Matthew F Pech, Calvin J Kuo & Steven E Artandi

  3. Department of Medicine, Columbia University, New York, New York, USA

    Natalia Papeta & Ali G Gharavi

  4. Department of Pathology, University of California San Francisco, San Francisco, California, USA

    Jean L Olson

  5. Department of Pathology, Columbia University, New York, New York, USA

    Vivette D D'Agati

  6. The Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California, USA

    Steven E Artandi

Authors
  1. Marina Shkreli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kavita Y Sarin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew F Pech
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalia Papeta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Woody Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephanie A Brockman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peggie Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eunice Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frank Kuhnert
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean L Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Calvin J Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ali G Gharavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Vivette D D'Agati
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Steven E Artandi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.S., K.Y.S., M.F.P., N.P., F.K., J.L.O., C.J.K., A.G.G., V.D.D.A. and S.E.A. designed the experiments and analyzed data; M.S., K.Y.S., M.F.P., N.P., F.K., W.C., S.A.B., P.C. and E.L. performed the experiments; and M.S. and S.E.A. wrote the manuscript.

Corresponding author

Correspondence to Steven E Artandi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1 and 2 (PDF 16123 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shkreli, M., Sarin, K., Pech, M. et al. Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nat Med 18, 111–119 (2012). https://doi.org/10.1038/nm.2550

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2550

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research