Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure
Jianchao Xu, Guoyong Li, Peili Wang, Heino Velazquez, Xiaoqiang Yao, Yanyan Li, Yanling Wu, Aldo Peixoto, Susan Crowley, Gary V. Desir
Jianchao Xu, Guoyong Li, Peili Wang, Heino Velazquez, Xiaoqiang Yao, Yanyan Li, Yanling Wu, Aldo Peixoto, Susan Crowley, Gary V. Desir
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Article Cardiology

Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure

Abstract

The kidney not only regulates fluid and electrolyte balance but also functions as an endocrine organ. For instance, it is the major source of circulating erythropoietin and renin. Despite currently available therapies, there is a marked increase in cardiovascular morbidity and mortality among patients suffering from end-stage renal disease. We hypothesized that the current understanding of the endocrine function of the kidney was incomplete and that the organ might secrete additional proteins with important biological roles. Here we report the identification of a novel flavin adenine dinucleotide–dependent amine oxidase (renalase) that is secreted into the blood by the kidney and metabolizes catecholamines in vitro (renalase metabolizes dopamine most efficiently, followed by epinephrine, and then norepinephrine). In humans, renalase gene expression is highest in the kidney but is also detectable in the heart, skeletal muscle, and the small intestine. The plasma concentration of renalase is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects. Renalase infusion in rats caused a decrease in cardiac contractility, heart rate, and blood pressure and prevented a compensatory increase in peripheral vascular tone. These results identify renalase as what we believe to be a novel amine oxidase that is secreted by the kidney, circulates in blood, and modulates cardiac function and systemic blood pressure.

Authors

Jianchao Xu, Guoyong Li, Peili Wang, Heino Velazquez, Xiaoqiang Yao, Yanyan Li, Yanling Wu, Aldo Peixoto, Susan Crowley, Gary V. Desir

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Renalase is a secreted amine oxidase. (A) Detection of renalase in cultu...
Renalase is a secreted amine oxidase. (A) Detection of renalase in culture medium of HEK293 cells transiently transfected with renalase cDNA. Control, secondary antibody alone. (B) Western blot analysis of human plasma using an anti-renalase antibody. Normal, plasma from individuals with normal renal function; Control protein, human recombinant renalase protein; ESRD, plasma from patients with ESRD receiving hemodialysis. (C) Renalase metabolizes catecholamines. Ten micrograms of GST-renalase fusion protein was used for each assay; amine oxidase is expressed as H2O2 production (nmol/mg/min). (D) Renalase activity is insensitive to known monoamine oxidase inhibitors. The renalase activity was assessed as described in C, with dopamine, epinephrine, and norepinephrine as substrates. The renalase activity was examined in the absence of inhibitor (Alone), in the presence of 1 μM clorgyline, or in the presence of 1 μM pargyline. Renalase activity is expressed as arbitrary fluorescence units/10 μg protein. In control studies, clorgyline (1 μM) and pargyline (1 μM) inhibited MAO-A activity by 83.9% ± 2.3% (n = 3) and 82.4% ± 1.9% (n = 3), respectively. (E) Affinity purification of human renalase. The anti-renalase polyclonal antibody was used to isolate protein from human urine. Lane 1: renalase from human urine; lane 2: control with secondary antibody alone.