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      Renalase Lowers Ambulatory Blood Pressure by Metabolizing Circulating Adrenaline

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          Abstract

          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 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.

          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. ( J Am Heart Assoc. 2012;1:e002634 doi: 10.1161/JAHA.112.002634.)

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          Most cited references17

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          Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity.

          We show here the identity of Alamar Blue as resazurin. The 'resazurin reduction test' has been used for about 50 years to monitor bacterial and yeast contamination of milk, and also for assessing semen quality. Resazurin (blue and nonfluorescent) is reduced to resorufin (pink and highly fluorescent) which is further reduced to hydroresorufin (uncoloured and nonfluorescent). It is still not known how this reduction occurs, intracellularly via enzyme activity or in the medium as a chemical reaction, although the reduced fluorescent form of Alamar Blue was found in the cytoplasm and of living cells nucleus of dead cells. Recently, the dye has gained popularity as a very simple and versatile way of measuring cell proliferation and cytotoxicity. This dye presents numerous advantages over other cytotoxicity or proliferation tests but we observed several drawbacks to the routine use of Alamar Blue. Tests with several toxicants in different cell lines and rat primary hepatocytes have shown accumulation of the fluorescent product of Alamar Blue in the medium which could lead to an overestimation of cell population. Also, the extensive reduction of Alamar Blue by metabolically active cells led to a final nonfluorescent product, and hence an underestimation of cellular activity.
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            Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts.

            During the last decades a large number of flavin-dependent monooxygenases have been isolated and studied. This has revealed that flavoprotein monooxygenases are able to catalyze a remarkable wide variety of oxidative reactions such as regioselective hydroxylations and enantioselective sulfoxidations. These oxidation reactions are often difficult, if not impossible, to be achieved using chemical approaches. Analysis of the available genome sequences has indicated that many more flavoprotein monooxygenases exist and await biocatalytic exploration. Based on the known biochemical properties of a number of flavoprotein monooxygenases and sequence and structural analyses, flavoprotein monooxygenases can be classified into six distinct flavoprotein monooxygenase subclasses. This review provides an inventory of known flavoprotein monooxygenases belonging to these different enzyme subclasses. Furthermore, the biocatalytic potential of a selected number of flavoprotein monooxygenases is highlighted.
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              Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure.

              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.
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                Author and article information

                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                ahaoa
                jah3
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                Blackwell Publishing Ltd
                2047-9980
                August 2012
                24 August 2012
                : 1
                : 4
                : e002634
                Affiliations
                From Yale University School of Medicine, Department of Medicine, New Haven, CT (G.V.D., L.Q.T., P.W., G.L., H.V.)
                VA Connecticut Healthcare System (VACHS) Medical Center, West Haven, CT (G.V.D., L.Q.T., P.W., G.L., H.V.)
                Nephrology Research and Development Unit, Faculty of Medicine and Dental Medicine, University of Porto, Hospital S. João, Porto, Portugal (B.S.-M., J.Q.-S., M.P.)
                Author notes
                Correspondence to: Gary Desir, MD, Section of Nephrology, Department of Medicine, Yale School of Medicine, PO Box 208029, New Haven, CT 06520‐8029. E‐mail gary.desir@ 123456yale.edu
                Article
                jah350
                10.1161/JAHA.112.002634
                3487338
                23130169
                b6033be4-b4e1-4b04-83b7-662d309cc913
                © 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell.

                This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 20 April 2012
                : 18 May 2012
                Categories
                Original Research
                Hypertension

                Cardiovascular Medicine
                catecholamines,kidney,norepinephrine,hypertension
                Cardiovascular Medicine
                catecholamines, kidney, norepinephrine, hypertension

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