Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation1. Recent identification of signaling cascades de-regulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking2,3. 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.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) affects up to 12 million individuals and is the 4th most common cause for renal replacement therapy worldwide. There have been many recent advances in the understanding of its molecular genetics and biology, and in the diagnosis and management of its manifestations. Yet, diagnosis, evaluation, prevention and treatment vary widely and there are no broadly accepted practice guidelines. Barriers to translation of basic science breakthroughs to clinical care exist, with considerable heterogeneity across countries. The KDIGO Controversies Conference on ADPKD brought together a panel of multi-disciplinary clinical expertise and engaged patients to identify areas of consensus, gaps in knowledge, and research and health care priorities related to diagnosis, monitoring of kidney disease progression, management of hypertension, renal function decline and complications, end-stage renal disease, extrarenal complications, and practical integrated patient support. These are summarized in this report.