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.

  • Letter
  • Published:

Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy

Nature Medicine volume 19, pages 488–493 (2013)Cite this article

Subjects

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation1. Recent identification of signaling cascades deregulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking2,3. Using a metabolomic approach, we identify a pathogenic pathway in this disease that can be safely targeted for therapy. We show that mutation of PKD1 results in enhanced glycolysis in cells in a mouse model of PKD and in kidneys from humans with ADPKD. Glucose deprivation resulted in lower proliferation and higher apoptotic rates in PKD1-mutant cells than in nondeprived cells. Notably, two distinct PKD mouse models treated with 2-deoxyglucose (2DG), to inhibit glycolysis, had lower kidney weight, volume, cystic index and proliferation rates as compared to nontreated mice. These metabolic alterations depend on the extracellular signal-related kinase (ERK) pathway acting in a dual manner by inhibiting the liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK) axis on the one hand while activating the mTOR complex 1 (mTORC1)-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop, restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a new therapeutic strategy using existing drugs, either individually or in combination.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Metabolomics analysis revealed higher aerobic glycolysis in Pkd1−/− MEFs.
Figure 2: Glucose dependence, defective autophagy and altered phosphorylation amounts of AMPK and ERK in Pkd1−/− cells.
Figure 3: Defective glycolysis and the ERK-AMPK axis in vivo.
Figure 4: Treatment with 2DG ameliorates cystic kidney disease in two ADPKD orthologous models.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Torres, V.E., Harris, P.C. & Pirson, Y. Autosomal dominant polycystic kidney disease. Lancet 369, 1287–1301 (2007).

    Article  Google Scholar 

  2. Harris, P.C. & Torres, V.E. Polycystic kidney disease. Annu. Rev. Med. 60, 321–337 (2009).

    Article  CAS  Google Scholar 

  3. Takiar, V. & Caplan, M.J. Polycystic kidney disease: pathogenesis and potential therapies. Biochim. Biophys. Acta 1812, 1337–1343 (2011).

    Article  CAS  Google Scholar 

  4. Grantham, J.J., Geiser, J.L. & Evan, A.P. Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int. 31, 1145–1152 (1987).

    Article  CAS  Google Scholar 

  5. Torres, V.E. et al. Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. Clin. J. Am. Soc. Nephrol. 5, 1312–1329 (2010).

    Article  CAS  Google Scholar 

  6. Distefano, G. et al. Polycystin-1 regulates extracellular signal-regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Mol. Cell Biol. 29, 2359–2371 (2009).

    Article  CAS  Google Scholar 

  7. Forseth, R.R. & Schroeder, F.C. NMR-spectroscopic analysis of mixtures: from structure to function. Curr. Opin. Chem. Biol. 15, 38–47 (2011).

    Article  CAS  Google Scholar 

  8. Garcia-Manteiga, J.M. et al. Metabolomics of B to plasma cell differentiation. J. Proteome Res. 10, 4165–4176 (2011).

    Article  CAS  Google Scholar 

  9. Vander Heiden, M.G., Cantley, L.C. & Thompson, C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  10. Düvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    Article  Google Scholar 

  11. Yecies, J.L. & Manning, B.D. Transcriptional control of cellular metabolism by mTOR signaling. Cancer Res. 71, 2815–2820 (2011).

    Article  CAS  Google Scholar 

  12. Chiaradonna, F. et al. From cancer metabolism to new biomarkers and drug targets. Biotechnol. Adv. 30, 30–51 (2012).

    Article  CAS  Google Scholar 

  13. Woo, D. Apoptosis and loss of renal tissue in polycystic kidney diseases. N. Engl. J. Med. 333, 18–25 (1995).

    Article  CAS  Google Scholar 

  14. Merrick, D. et al. The γ-secretase cleavage product of polycystin-1 regulates TCF and CHOP-mediated transcriptional activation through a p300-dependent mechanism. Dev. Cell 22, 197–210 (2012).

    Article  CAS  Google Scholar 

  15. Choo, A.Y. et al. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol. Cell 38, 487–499 (2010).

    Article  CAS  Google Scholar 

  16. Zheng, B. et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol. Cell 33, 237–247 (2009).

    Article  CAS  Google Scholar 

  17. Shibazaki, S. et al. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum. Mol. Genet. 17, 1505–1516 (2008).

    Article  CAS  Google Scholar 

  18. Song, X. et al. Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum. Mol. Genet. 18, 2328–2343 (2009).

    Article  CAS  Google Scholar 

  19. Foxall, P.J. et al. High resolution proton magnetic resonance spectroscopy of cyst fluids from patients with polycystic kidney disease. Biochim. Biophys. Acta 1138, 305–314 (1992).

    Article  CAS  Google Scholar 

  20. Yu, S. et al. Essential role of cleavage of polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure. Proc. Natl. Acad. Sci. USA 104, 18688–18693 (2007).

    Article  CAS  Google Scholar 

  21. Csibi, A. & Blenis, J. Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors. BMC Biol. 9, 69 (2011).

    Article  CAS  Google Scholar 

  22. Shillingford, J.M. et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. USA 103, 5466–5471 (2006).

    Article  CAS  Google Scholar 

  23. Shillingford, J.M., Piontek, K.B., Germino, G.G. & Weimbs, T. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J. Am. Soc. Nephrol. 21, 489–497 (2010).

    Article  CAS  Google Scholar 

  24. Serra, A.L. et al. Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study. BMC Nephrol. 8, 13 (2007).

    Article  Google Scholar 

  25. Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830–840 (2010).

    Article  CAS  Google Scholar 

  26. Serra, A.L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820–829 (2010).

    Article  CAS  Google Scholar 

  27. McCarty, M.F., Barroso-Aranda, J. & Contreras, F. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease. Med. Hypotheses 73, 1008–1010 (2009).

    Article  CAS  Google Scholar 

  28. Takiar, V. et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl. Acad. Sci. USA 108, 2462–2467 (2011).

    Article  CAS  Google Scholar 

  29. Cheong, J.H. et al. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol. Cancer Ther. 10, 2350–2362 (2011).

    Article  CAS  Google Scholar 

  30. Bastos, A.P. et al. Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. J. Am. Soc. Nephrol. 20, 2389–2402 (2009).

    Article  CAS  Google Scholar 

  31. Wodarczyk, C. et al. Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. PLoS ONE 5, e12719 (2010).

    Article  Google Scholar 

  32. Wodarczyk, C. et al. A novel mouse model reveals that polycystin-1 deficiency in ependyma and choroid plexus results in dysfunctional cilia and hydrocephalus. PLoS ONE 4, e7137 (2009).

    Article  Google Scholar 

  33. Shao, X., Somlo, S. & Igarashi, P. Epithelial-specific Cre/lox recombination in the developing kidney and genitourinary tract. J. Am. Soc. Nephrol. 13, 1837–1846 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank other members of the lab Boletta and G. Di Grigoli for helpful discussion, R.M. Moresco for helpful suggestions and critically reading the manuscript, G. Casari and L. Cassina for help with the experiments on mitochondria, M. Giorgio for analysis of oxygen consumption and the San Raffaele microscopy facility (Alembic) for the electron microscopy studies (M.C. Panzeri) and tetramethylrhodamine (TMRM) analysis (M. Ascagni). V.M. is a student in the PhD Program of Biochemical, Nutritional and Metabolic Sciences, University of Milan. This work was supported by Telethon-Italy (TCR05007 to A.B. and TCP99035 to G.M.), US National Institutes of Health grants DK62199 (to F.Q.) and DK090868 (Johns Hopkins Polycystic Kidney Disease Research and Clinical Core Center, P30) and the Canadian Institutes of Health Research grant MOP123429 (to Y.P.). A.B. and G.M. are Associate Telethon Scientists. The lab Boletta is especially indebted to S. Bramani for her continuous, intelligent and motivating support.

Author information

Author notes

  1. Hangxue Xu, Silvia Mari & Feng Qian

    Present address: Present addresses: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA (H.X. and F.Q.) and Research 4 Rent, Rodano, Milan, Italy (S.M.).,

Authors and Affiliations

  1. Division of Genetics and Cell Biology, Dulbecco Telethon Institute (DTI) at Dibit, San Raffaele Scientific Institute, Milan, Italy

    Isaline Rowe, Marco Chiaravalli, Valeria Ulisse, Monika Pema & Alessandra Boletta

  2. Biomolecular NMR Laboratory, DTI at the Center of Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy

    Valeria Mannella, Giacomo Quilici, Silvia Mari & Giovanna Musco

  3. Division of Nephrology, University of Toronto, Toronto, Ontario, Canada

    Xuewen W Song & York Pei

  4. Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Hangxue Xu & Feng Qian

Authors
  1. Isaline Rowe
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Marco Chiaravalli
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Valeria Mannella
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Valeria Ulisse
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Giacomo Quilici
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Monika Pema
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Xuewen W Song
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Hangxue Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Silvia Mari
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Feng Qian
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. York Pei
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Giovanna Musco
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Alessandra Boletta
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

I.R. designed and performed the experiments, interpreted them and wrote the manuscript. M.C. designed and performed the in vivo experiments with 2DG treatment and 13-C glucose injections and interpreted the results. V.U. performed experiments in vitro on autophagy and signaling. M.P. generated the Ksp-Cre; Pkd1 mice, analyzed the kidneys biochemically and performed quantitative RT-PCR. A.B. designed the studies, supervised the work and collaborations and wrote the manuscript. V.M. prepared samples for metabolomic analysis, analyzed NMR spectra and performed statistical analysis. G.Q. acquired NMR spectra and performed statistical analysis. S.M. prepared samples for metabolomic analysis, acquired and analyzed NMR spectra and performed statistical analysis. G.M. supervised metabolomic analysis and discussed results. X.W.S. and Y.P. designed, performed and interpreted the human PKD1 renal cyst microarray experiment. H.X. and F.Q. designed and carried out the 2DG treatment experiment of Pkd1V/V mice and analyzed and interpreted the resulting data.

Corresponding authors

Correspondence to Giovanna Musco or Alessandra Boletta.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Table 1 and Supplementary Methods (PDF 6337 kb)

Supplementary Table 2

Glycolytic gene expression in cystic as compared to minimally cuystic or normal renal tissues (XLS 62 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rowe, I., Chiaravalli, M., Mannella, V. et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 19, 488–493 (2013). https://doi.org/10.1038/nm.3092

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3092

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