Defective Glucose Metabolism in Polycystic Kidney Disease Identifies A Novel Therapeutic Paradigm

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation ¹ . Recent identification of signaling cascades de-regulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking ^{2, 3} . Using a metabolomic approach here we identify a pathogenic pathway in ADPKD which can be safely targeted for therapy. We show that mutation in PKD1 results in enhanced glycolysis in cells, in a murine model of PKD, and in human-derived ADPKD kidneys. Glucose deprivation reduced proliferation and sensitized PKD1 mutant cells to apoptosis. Notably, treatment of two distinct PKD mouse models with 2-deoxyglucose (2DG) ameliorates kidney volume, cystic index and reduced proliferation rates. These metabolic alterations depend on the ERK pathway acting in a dual manner by inhibiting the LKB1-AMPK axis on the one hand while activating the 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 novel therapeutic paradigm using existing drugs, either individually or in combination.