The catalytic function of renalase: A decade of phantoms

Abstract

Ten years after the initial identification of human renalase the first genuinely catalytic substrates have been identified. Throughout the prior decade a consensus belief that renalase is produced predominantly by the kidney and catalytically oxidizes catecholamines in order to lower blood pressure and slow the heart has prevailed. This belief was, however, based on fundamentally flawed scientific observations that did not include control reactions to account for the well-known autoxidation of catecholamines in oxygenated solutions. Nonetheless, the initial claims have served as the kernel for a rapidly expanding body of research largely predicated on the belief that catecholamines are substrates for this enzyme. The proliferation of scientific studies pertaining to renalase as a hormone has proceeded unabated despite well-reasoned expressions of dissent that have indicated the deficiencies of the initial observations and other inconsistencies. Our group has very recently identified isomeric forms of β-NAD(P)H as substrates for renalase. These substrates arise from non-specific reduction of β-NAD(P)(+) that forms β-4-dihydroNAD(P) (β-NAD(P)H), β-2-dihydroNAD(P) and β-6-dihydroNAD(P); the latter two being substrates for renalase. Renalase oxidizes these substrates with rate constants that are up to 10(4)-fold faster than any claimed for catecholamines. The electrons harvested are delivered to dioxygen via the enzyme's FAD cofactor forming both H2O2 and β-NAD(P)(+) as products. It would appear that the metabolic purpose of this chemistry is to alleviate the inhibitory effect of β-2-dihydroNAD(P) and β-6-dihydroNAD(P) on primary metabolism dehydrogenase enzymes. The identification of this genuinely catalytic activity for renalase calls for re-evaluation of much of the research of this enzyme, in which definitive links between renalase catecholamine consumption and physiological responses were reported. This article is part of a Special Issue entitled: Physiological enzymology and protein functions.

Effects of Renin-Angiotensin System Inhibitors on Renal Expression of Renalase in Sprague-Dawley Rats Fed With High Salt Diet

“…Whether renalase is an amine oxidase or not is presently debated. Aliverti and Moran et al [6,7,8] failed to demonstrate the catalytic activity of renalase, which is contradictory to the investigation reported by Xu et al [1]. Thus, additional evidence is needed to confirm whether renalase is an amine oxidase.…”

Levels of renalase and advanced oxidation protein products with regard to catecholamines in haemodialysed patients

“…Wang et al [37] showed that renalase promoted cell survival and protected against renal ischaemia reperfusion injury in mice through the activation of intracellular signalling cascades, independent of its ability to degrade catecholamines. More recently, Moran et al [38] found that, in fact, renalase does bind to , and performs no catalyic transformation of A [39]. Quelhas-Santos et al [40] reported that renalase degrades catecholamines catalyzing the formation of aminochromes.…”

“…Recently discovered as a new renal hormone, renalase -flavin adenine dinucleotide (FAD) -dependent amine oxidase [3,4,5], is secreted by the kidneys and can metabolize the circulating CA and possibly play an important role in the regulation of sympathetic tone and blood pressure. The concept that renalase might be involved in the regulation of blood pressure is supported by the fact that the inactivation of the RNLS gene in mice by homologous recombination is associated with an elevated blood pressure, and a sympathetic activity in the absence of other measurable changes in renal function [6,7,8].…”

Renalase Secreted by Human Kidney HEK293T Cells Lacks its N-Terminal Peptide: Implications for Putative Mechanisms of Renalase Action

“…Possible mechanisms of renalase action that would account for the decrease of blood pressure remain elusive [4][5][6]. Nevertheless, administration of recombinant human renalase lowered arterial pressure in Sprague-Dawley rats [1,7].…”

“…Renalase is a recently discovered secretory protein involved in regulation of blood pressure [1][2][3][4][5][6]. Possible mechanisms of renalase action that would account for the decrease of blood pressure remain elusive [4][5][6].…”