Renalase Lowers Ambulatory Blood Pressure by Metabolizing Circulating Adrenaline

Background-Blood 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 Results-Using 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 alpha-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. Conclusions-Renalase 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.