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

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

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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.

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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.

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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.

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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

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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.

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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)

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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

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