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.

[1]  A. Mattevi,et al.  Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations , 2002, The Journal of Biological Chemistry.

[2]  S. Jalkanen,et al.  VAP-1: an adhesin and an enzyme. , 2001, Trends in immunology.

[3]  H. Humes Acute renal failure: prevailing challenges and prospects for the future. , 1995, Kidney international. Supplement.

[4]  C. V. Van Itallie,et al.  Claudins create charge-selective channels in the paracellular pathway between epithelial cells. , 2002, American journal of physiology. Cell physiology.

[5]  J. Morrow,et al.  Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. , 2004, Kidney international.

[6]  C. Zoccali,et al.  Plasma Norepinephrine Predicts Survival and Incident Cardiovascular Events in Patients With End-Stage Renal Disease , 2002, Circulation.

[7]  Robert M Califf,et al.  Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. , 2004, The New England journal of medicine.

[8]  B. Brenner,et al.  Determinants of glomerular filtration rate. , 1976, Annual review of physiology.

[9]  P. Persson Renin: origin, secretion and synthesis , 2003, Journal of Physiology.

[10]  T. Hostetter Chronic kidney disease predicts cardiovascular disease. , 2004, The New England journal of medicine.

[11]  M. Paulais,et al.  Extracellular urea concentration modulates cAMP production in the mouse MTAL. , 1996, Kidney international.

[12]  Humes Hd Acute renal failure: prevailing challenges and prospects for the future. , 1995 .

[13]  C. H. Lin,et al.  Cloning and expression of the human erythropoietin gene. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C. Zoccali,et al.  Norepinephrine and Concentric Hypertrophy in Patients With End-Stage Renal Disease , 2002, Hypertension.

[15]  A. S. Segal,et al.  Regulation of the voltage-gated K+ channel KCNA10 by KCNA4B, a novel beta-subunit. , 2002, American journal of physiology. Renal physiology.

[16]  Charles E McCulloch,et al.  Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. , 2004, The New England journal of medicine.

[17]  S. Jalkanen,et al.  Cell surface monoamine oxidases: enzymes in search of a function , 2001, The EMBO journal.

[18]  O. Zelphati,et al.  Transcriptionally Active Polymerase Chain Reaction (TAP) , 2002, The Journal of Biological Chemistry.

[19]  R D Klausner,et al.  The mammalian gene collection. , 1999, Science.

[20]  A. S. Segal,et al.  Regulation of the voltage-gated K+ channel KCNA10 by KCNA4B, a novel β-subunit , 2002 .

[21]  J. Joles,et al.  Causes and Consequences of Increased Sympathetic Activity in Renal Disease , 2004, Hypertension.

[22]  K. Rahn,et al.  Sympathetic Nerve Activity in End-Stage Renal Disease , 2002, Circulation.

[23]  Andrea Mattevi,et al.  Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders , 2002, Nature Structural Biology.

[24]  G. Desir,et al.  Expression of KCNA10, a voltage-gated K channel, in glomerular endothelium and at the apical membrane of the renal proximal tubule. , 2002, Journal of the American Society of Nephrology : JASN.

[25]  Eld,et al.  COMPARISON OF MORTALITY IN ALL PATIENTS ON DIALYSIS , PATIENTS ON DIALYSIS AWAITING TRANSPLANTATION , AND RECIPIENTS OF A FIRST CADAVERIC TRANSPLANT , 2000 .

[26]  E. Fritsch,et al.  Isolation and characterization of genomic and cDNA clones of human erythropoietin , 1985, Nature.

[27]  P. Blankestijn,et al.  J Am Soc Nephrol 15: 524–537, 2004 Sympathetic Hyperactivity in Chronic Renal Failure: A Wakeup , 2022 .