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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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.
The authors declare no competing financial interests.
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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) doi:10.1038/nm.3092
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