The renalase pathway is a previously unrecognized mechanism for regulating cardiac function and blood pressure. In this pathway, renalase, a novel secreted amine oxidase that is inactive at baseline, is rapidly turned on ( ~ 10 fold increase) by either a modest increase in blood pressure or by brief surges in plasma catecholamines. The active enzyme degrades circulating catecholamines, causing a significant fall in blood pressure. Plasma catecholamines not only activate renalase enzymatic activity but also lead to a 3-4 fold stimulation of renalase secretion. The renalase knockout mouse (KO) is hypertensive and exquisitely sensitive to cardiac ischemia. Abnormalities in the renalase pathway are present in animal models of chronic kidney disease (CKD) and hypertension. Two single-nucleotide polymorphisms (SNPs) 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 are markedly reduced in patients with end-stage kidney disease (ESRD). We hypothesize that renalase is secreted into blood by the kidney (although also expressed in heart, skeletal muscle, and small intestine) and plays 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 CKD.