Renalase is a FAD-dependent amine oxidase.
Called also MAO-C, renalase has 13% and 12% identity at the amino acid level to MAO-A and MAO-B, respectively. It also has a distinct substrate specificity and inhibitor profile to that of MAO-A and MAO-B, indicating that it represents a brand new class of unique FAD-containing monoamine oxidases.
The human renalase gene resides on chromosome 10, contains 9 exons and spans about 311 Kb.
CHEMICAL STRUCTURE AND IMAGES
The human renalase gene encodes a 342-amino acid protein that contains an amino-terminal signal sequence, followed by a flavin-adenosine-dinucleotide (FAD)- containing domain and an amino oxidase domain. Human renalase cDNA is translated to produce a protein with a molecular mass of 37,8-kDa. The nucleic acid sequence of human renalase is 27.7% homologous to that of human MAO-A and 38.2% homologous to that of MAO-B(isoforms).
Amine oxidases are enzymes that metabolize biogenic amines and are classified according to the nature of the attached cofactor, such as FAD or topaquinone(TPQ). MAO-A and MAO-B are FAD-containing, mitochondrial enzymes that metabolize intracellular catecholamines. The crystal structure of human MAO-B has been determined at a resolution of 3.0 Å and reveals a dimer with the FAD cofactor covalently bound to a cysteine side chain (Cys-397).
MAO-A and MAO-B have overlapping substrate specificity; catabolize neurotransmitters such as epinephrine, norepinephrine, serotonin, and dopamine; and are specifically inhibited by clorgyline and deprenyl, respectively while neither MAO-A nor MAO-B inhibitors (pargyline and clorgyline, respectively) could block renalase. Unlike MAO-A and MAO-B, which are anchored through the carboxyl terminus to the outer mitochondrial membrane and confined to intracellular compartments, renalase is secreted into the blood, where it is detectable by Western blotting.
Renalase Aminoacids %
SYNTHESIS AND TURNOVER
Renalase is a protein secreted by the kidney into the blood(in humans, renalase gene expression is highest here, but is also detectable in the heart, skeletal muscle, and the small intestine)and has a catecholamine-metabolising activity (it metabolizes dopamine most efficiently, followed by epinephrine, and then norepinephrine).
The claim of catecholamine-metabolising activity of renalase was based on the generation of H2O2 during incubation of the enzyme with catecholamines. It is critically dependent on FAD for oxidase activity, since the protein is inactive unless the cofactor is incorporated during protein production.
Renalase, in conjunction with MAO-A and MAO-B that catabolize intracellular amines, is an important enzyme to oxidase extracellular catecholamine, and thus contributing to the regulation of overall sympathetic tone.
Renalase is most abundant in the proximal tubules and it presents in the circulation of normal individuals, suggesting that renalase protein in the proximal tubules can be secreted via the basolateral membrane into the circulation where it catabolized its substrate(s), and thus, regulating catecholamine homeostasis at a systemic level. It is possible that renalase also exerts its biological function at the lumen of renal tubules, since renalase is small protein which can be easily filtered to the lumen of nephron. In addition, renalase can be directly secreted via the apical membrane by the proximal tubules, where it metabolize its substrate(s) that filtered through the glomeruli and generated de novo by the renal tubular cells such as dopamine. The significance of renalase in catecholamine metabolism at intra-lumen is to regulate intra-lumen catecholamine level, thus regulating salt and water re-absorption.
Clinical tests on rats showed that intravenous renalase decreased their blood pressures
by 25%; the effect dissipated within minutes. Heart rate decreased accordingly, as did cardiac contractility. The effects were dose dependent. The animals behaved as if they had been suddenly subjected to a massive α and β adrenoceptor blockade.
Renalase is a secreted protein which circulates in an inactive form (prorenalase). Prorenalase is rapidly (30-60 s) activated by increased plasma catecholamines and systolic blood pressure,
and converted to renalase, which in turn degrades catecholamines.
Catecholamine administration promotes the secretion of preformed renalase within 5 min. Plasma renalase is markedly reduced in patients with chronic kidney disease and end-stage renal disease, and in animal models of chronic kidney disease and salt-dependent hypertension. Rats subjected to subtotal nephrectomy develop hypertension and chronic kidney disease, and exhibit low plasma and cardiac renalase, and abnormal renalase activation.
Patients who develop end-stage renal disease(ESRD) are either treated with replacement therapy, such as peritoneal or hemodialysis, or receive a renal transplant.
Despite the success of dialysis in prolonging life, the morbidity and mortality associated with this therapy remain high, and most patients experience a poor quality of life.
The reasons for this are not entirely clear. For instance,it is well documented that patients with ESRD are at significantly higher risk for developing cardiovascular disease, a risk that appears to be correlated with increased oxidative stress and heightened sympathetic tone.
Parenteral administration of either native or recombinant renalase lowers blood pressure and heart rate by metabolizing circulating catecholamines(which are important mediators for the function of the kidney, heart and blood vessels).
Like EPO, renalase is virtually non-detectable in patients with ESRD, whereas it is expressed in the blood of healthy individuals at concentration of about 5-10mg/L. While renalase deficiency occurs in salt-sensitive rats as they develop hypertension, renalase inhibition by antisense RNA increases baseline blood pressure, and leads to an exaggerated blood pressure response to adrenergic stress.
So the correlation between renalase levels and renal function make renalase an ideal candidate for a diagnostic marker for renal disease. Its identification also has important implications in the development of therapeutics and diagnostics for end-stage renal diseases (ESRD) to treat/prevent hypertension, cardiovascular diseases such as asymptomatic left ventricular dysfunction, chronic congestive heart failure and atherosclerosis.
Thus it’s possible to identify a human patient afflicted with a disease, disorder or condition associated with altered expression of renalase detecting the level of renalase expression and comparing it with the level of expression of renalase in a normal human not afflicted with a disease, disorder or condition associated with altered expression of renalase(or increased sympathetic output).
Collectively, these data suggest that renalase plays a key role in the regulation of sympathetic tone, blood pressure and cardiac function.
The identification of renalase is not only an important step in development of a more detailed understanding of cardiovascular physiology, but also an important step in the quest for providing optimal treatment for patients with kidney disease and/or heart disease and their related complications.