RENALASE DEFICIENCY AND CARDIOVASCULAR COMPLICATIONS OF CHRONIC KIDNEY DISEASE

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The challenge area (15-DK-103) is the translation of new molecules and pathways involved in pathogenesis of diseases of interest to NIDDK into potential therapies, diagnostics, or research tools. The specific challenge topic is the examination of the therapeutic utility of renalase, a novel molecule discovered in our laboratory, for the treatment of cardiovascular complications associated with chronic kidney disease. Twenty million Americans suffer from chronic kidney disease, and are at significantly greater risk for having both fatal and non-fatal cardiovascular complications. The pathogenesis of cardiac disease in this patient population is not well understood. Patients with kidney disease have a deficiency in renalase, a newly discovered enzyme that is made in the kidney, is secreted in blood, and regulates blood pressure and cardiac function. The renalase pathway is a previously unrecognized mechanism for regulating circulating catecholamines, and, therefore, cardiac function, and blood pressure. In this pathway, renalase, a novel secreted amine oxidase that is inactive at baseline, is rapidly turned on (25 fold increase) by either modest increases in blood pressure and/or brief surges in either plasma dopamine, epinephrine or norepinephrine. The active enzyme specifically degrades circulating catecholamines in vivo, causing a significant fall in blood pressure even in normotensive animals. An increase in plasma catecholamines, not only activates renalase enzymatic activity, but also leads to a 3-4 stimulation of renalase secretion. We have preliminary evidence suggesting the presence of a renalase inhibitor in plasma. The renalase knockout mouse (renalase KO) is hypertensive. Abnormalities in the renalase pathway are evident in animal models of chronic kidney disease (CKD) and hypertension. Two single nucleotide polymorphisms (SNP) in the renalase gene were found to be associated with essential hypertension in man. Blood renalase levels are inversely correlated with glomerular filtration rate (GFR) and markedly reduced in patients with advanced CKD, and end stage kidney disease (ESRD). The sympathetic nervous system is activated in CKD and ESRD, and patients have a significant increase in cardiovascular disease. We hypothesize that intracellular renalase along with that secreted into blood by the kidney (although also expressed in heart, skeletal muscle and small intestine), play a key role in regulating blood pressure and cardiovascular function, and that abnormalities in the renalase pathway contribute to the heightened cardiovascular risks observed in patients with chronic kidney disease (CKD). Based on the foregoing, we hypothesize that both intracellular and secreted renalase play a key role in regulating blood pressure and cardiovascular function, and that abnormalities in the renalase pathway contribute to the heightened cardiovascular risks observed in patients with chronic kidney disease (CKD). In the context of the overall hypothesis, we propose to examine the molecular mechanisms by which renalase deficiency predisposes to more severe ischemic renal and cardiac injury, and to explore the therapeutic utility of recombinant renalase These studies will expand our knowledge of the renalase pathway, and may identify novel therapeutic targets for the prevention and treatment of cardiovascular complications in patients with kidney disease. PUBLIC HEALTH RELEVANCE: Twenty million Americans suffer from chronic kidney disease, and are at significantly greater risk for having both fatal and non-fatal cardiovascular complications. The pathogenesis of cardiac disease in this patient population is not well understood. Patients with kidney disease have a deficiency in renalase, a newly discovered hormone that is made in the kidney, is secreted in blood, and regulates blood pressure and cardiac function. Renalase itself or components of the renalase pathway may offer valuable therapeutic options for patients with kidney disease.