Review Article Renalase is a novel renal hormone that regulates cardiovascular function Gary V. Desir, MD Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA, and VACHS Medical Center, West Haven, Connecticut, USA Manuscript received and accepted December 5, 2006 Abstract Patients with chronic kidney disease suffer from a significant increase in cardiovascular morbidity and mortality. While the reasons for this observation are not entirely clear, it is generally accepted that current methods of renal replacement therapy do not adequately mimic the various roles of the kidney, and that the diseased kidney may generate signals that affect other systems with detrimental consequences. We hypothesized that the kidney synthesized proteins, which were unrecognized, but were secreted in the circulation and modulated the cardiovascular system. To gain a fuller understanding of the process, we embarked on a search for novel, secreted renal proteins, using a number of complementary approaches. We identified a flavin adenine dinucleotide-dependent amine oxidase (renalase) that is made and secreted by the kidney. Renalase blood levels are easily measured in healthy subjects, but are markedly reduced in patients with end-stage renal disease. In vitro studies indicate that renalase is a novel amine oxidase that specifically metabolizes circulating catecholamines including epinephrine and norepinephrine. Renalase infusion leads to a decrease in cardiac contractility, heart rate, and blood pressure and prevented a compensatory increase in peripheral vascular tone. These results identify renalase as a novel renal hormone that modulates cardiac function and systemic blood pressure by regulating catecholamine levels. Since patients with chronic kidney disease have increased sympathetic tone and decreased renalase blood level, we speculate that renalase administration will improve cardiovascular outcome in this patient population. © 2007 American Society of Hypertension. All rights reserved. Keywords: Blood pressure regulation; amine oxidase; catecholamines metabolism; renal failure. The Kidney as an Endocrine Organ The regulation of fluid and electrolyte metabolism is a major function of the kidney, which filters out cells and proteins and generates, through a process called glomerular filtration, a fluid with an ionic composition identical to that of plasma. The glomerular filtrate then travels through a series of distinct tubular segments, which progressively modify its volume and ionic composition. A large number of factors are known to regulate glomerular filtration includ- ing physical forces, local and systemic hormones. 1 Simi- larly, renal tubular reabsorption and secretion are modified by rather complex regulatory processes. The kidney also serves as an endocrine organ. Indeed, it is the primary source of erythropoietin, a key determinant of red cell mass required for expansion and differentiation of erythroid progenitors and precursors. 2,3 It is also the most important site for renin release. 4 A fall in blood flow, increased sympathetic stimulation, or a decrease in sodium chloride delivery to the distal tubules can stimulate the release of renin, an enzyme that cleaves angiotensinogen to angiotensin I. The renin-angiotensin system is an important regulator of fluid and electrolyte balance, systemic blood pressure, and cardiovascular function. Cardiovascular Complications in Chronic Kidney Disease (CKD) Patients who develop end-stage renal disease (ESRD) are either treated with replacement therapy, such as peritoneal or hemodialysis, or given a renal transplant. Despite the success of dialysis at prolonging life, the morbidity and mortality This article was supported by the Veterans’ Administration (Merit Review award) and by the NIH (DK48105B). Conflict of interest: none. Corresponding author: Gary V. Desir, MD, Section of Nephrol- ogy, Department of Medicine, Yale School of Medicine, 333 Cedar Street, LMP 2073, P.O. Box 208029, New Haven, Connect- icut 06520. Tel.: 203-932-5711 ext. 2542. E-mail: gary.desir@yale.edu Journal of the American Society of Hypertension 1(2) (2007) 99 –103 1933-1711/07/$ – see front matter © 2007 American Society of Hypertension. All rights reserved. doi:10.1016/j.jash.2006.12.001