Renalase Lowers Ambulatory Blood Pressure by Metabolizing Circulating Adrenaline

Abstract

BackgroundBlood pressure is acutely regulated by the sympathetic nervous system through the action of vasoactive hormones such as epinephrine, norepinephrine, and dopamine. Renalase, a recently described, secreted flavoprotein, acutely decreases systemic pressure when administered in vivo. Single‐nucleotide polymorphisms present in the gene are associated with hypertension, cardiac disease, and diabetes. Although renalase's crystal structure was recently solved, its natural substrate(s) remains undefined.Methods and ResultsUsing in vitro enzymatic assays and in vivo administration of recombinant renalase, we show that the protein functions as a flavin adenine dinucleotide– and nicotinamide adenine dinucleotide–dependent oxidase that lowers blood pressure by degrading plasma epinephrine. The enzyme also metabolizes the dopamine precursor l‐3,4‐dihydroxyphenylalanine but has low activity against dopamine and does not metabolize norepinephrine. To test if epinephrine and l‐3,4‐dihydroxyphenylalanine were renalase's only substrates, 17 246 unique small molecules were screened. Although the search revealed no additional, naturally occurring compounds, it identified dobutamine, isoproterenol, and α‐methyldopa as substrates of renalase. Mutational analysis was used to test if renalase's hypotensive effect correlated with its enzymatic activity. Single–amino acid mutations that decrease its enzymatic activity to varying degrees comparably reduce its hypotensive effect.ConclusionsRenalase metabolizes circulating epinephrine and l‐3,4‐dihydroxyphenylalanine, and its capacity to decrease blood pressure is directly correlated to its enzymatic activity. These findings highlight a previously unrecognized mechanism for epinephrine metabolism and blood pressure regulation, expand our understanding of the sympathetic nervous system, and could lead to the development of novel therapeutic modalities for the treatment of hypertension. (J Am Heart Assoc. 2012;1:e002634 doi: 10.1161/JAHA.112.002634.)

Renalase might be associated with hypertension and insulin resistance in Type 2 diabetes

“…[1][2][3] As a biological macromolecule strongly associated with the sympathetic nervous system, renalase has been intensively studied since its discovery. [4][5][6] Insulin resistance (IR) is a key feature of type 2 diabetes mellitus (T2DM). 7 In some T2DM patients, CA levels in blood circulation are increased.…”

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

“…They hypothesized that in this condition a more activated renalase was synthesized to cope with the increased NA levels. Recently, renalase was suggested to preferentially metabolize the circulating A, and its capacity to decrease blood pressure is directly correlated to this particular enzymatic activity [29,30]. However, to metabolize A, renalase uses a mechanism that is different from that exhibited by the monoamine oxidase (MAO).…”

Renalase — a new marker or just a bystander in cardiovascular disease: clinical and experimental data

“…Renalase is related to monoamine oxidase A with only 13% of amino acid identity [1]. As mentioned before, renalase is supposed to metabolise circulating in blood catecholamines, but its activity against dopamine, epinephrine, and norepinephrine remains unclear [1,13]. Moreover, renalase activity measurements need further explanation.…”

“…Wu et al [12] noticed that renalase knock-out mouse was hypertensive and tachycardiac and had higher catecholamine levels compared to wild type mouse. One year later Desir et al [13] observed a fall in blood pressure after subcutaneous administration of renalase in 5/6 nephrectomised rats. The same effect was observed after administration of 5 mg/kg enalapril.…”

“…Desir et al [13] suggested that renalase was an amine oxidase that contains a FAD-binding region. Renalase is related to monoamine oxidase A with only 13% of amino acid identity [1].…”