Catecholamines Regulate the Activity, Secretion, and Synthesis of Renalase

Abstract

Background-We previously identified renalase, a secreted novel amine oxidase that specifically degrades circulating catecholamines. Parenteral administration of either native or recombinant renalase lowers blood pressure, heart rate, and cardiac contractility by metabolizing circulating catecholamines. Renalase plasma levels are markedly reduced in patients with chronic kidney disease. It is not known whether endogenous renalase contributes to the regulation of catecholamines. Methods and Results-We show here that circulating renalase lacks significant amine oxidase activity under basal conditions (prorenalase) but that a brief surge of epinephrine lasting Ͻ2 minutes causes renalase activity to increase from 48Ϯ18 to 2246Ϯ98 arbitrary units (nϭ3; PϽ0.002). Enzyme activation is detectable within 30 seconds and sustained for at least 60 minutes. Analysis of epinephrine-mediated hemodynamic changes in normotensive rats indicates that prorenalase becomes maximally activated when systolic pressure increases by Ͼ5 mm Hg. The catecholamine surge also leads to a 2.8-fold increase in plasma renalase concentration. Cultured cells exposed to dopamine upregulate steady-state renalase gene expression by Ͼ10-fold. The time course of prorenalase activation is abnormal in rats with chronic kidney disease. Conclusions-These data identify a novel mechanism for the regulation of circulating catecholamines. In the renalase pathway, excess catecholamine facilitates the conversion of prorenalase, an inactive plasma amine oxidase, to renalase, which can degrade catecholamines. Excess catecholamines not only regulate the activation of prorenalase but also promote its secretion and synthesis. Because chronic kidney disease is associated with a number of systemic abnormalities, including activation of the sympathetic nervous system, increased catecholamines levels, cardiac hypertrophy, and hypertension, renalase replacement is an attractive therapeutic modality owing to its role in catecholamine metabolism.

Is Renalase a Novel Player in Catecholaminergic Signaling? The Mystery of the Catalytic Activity of an Intriguing New Flavoenzyme

“…First of all, as mentioned above, renalase 1 was detected in body fluids such as blood plasma and urine [1,10,29,30]. Secondly, in patients suffering from chronic kidney disease and primary glomerulonephritis, as well as in animal model of kidney failure, extracellular renalase was absent or present at lower concentrations, indicating the kidneys as the main source of the secreted protein [1,[30][31][32].…”

“…Subsequently, Desir's group proposed a catecholamine-triggered activation mechanism for circulating renalase, which would exist in inactive form under normal condition [29]. These authors reported that, while amine oxidase activity is undetectable in rat plasma under basal conditions, a 2 min infusion with epinephrine or dopamine determined the rapid (<1 min) onset of renalase activity (assayed as H 2 O 2 production specifically inhibited by an antirenalase antibody) that lasted for several minutes.…”

“…Consistent with this finding, they also observed that urine human renalase displays a much higher turnover rate than the plasma form. Since blood plasma was found to have a strong inhibitory effect on purified urine renalase, they concluded that circulating prorenalase might represents a resting enzyme form, possibly complexed with a specific inhibitor [8,18,29].…”

The Possible Role of Renalase Enzyme in Cardiovascular Complications in Chronic Kidney Disease Patients

“…According to the studies which suggested that renalase is secreted by renal cells since it was detected in both plasma and urine of healthy individuals [12,13]. Expression of renalase in peripheral nerves, adrenals, endothelium, and the central nervous system, as well as in adipose tissues, was detected both in 12.5-day-old rat embryo, and more recently, in humans [12,14]. The decrease in BP by 25% as well as a decrease in heart rate and cardiac contractility are the main actions of renalase [6].…”

“…The latter had hypertension, tachycardia, and catecholamine levels higher than the wild-type animal, therefore the knock-out mouse was reported to be more susceptible to myocardial ischemia [15]. It was also found by Li et al 2008 that renalase deficiency worsened myocardial damage during acute ischemia and the use of the recombinant renalase as treatment could ameliorate cardiac injury [12].…”