Renalase (gene name RNLS) is a recently discovered enzyme with monoamine oxidase activity implicated in the degradation of catecholamines and probably other currently unknown substrates [1, 2].
The human RNLS maps on chromosome 10 at q23.33 and has 10 exons which leads to the production of at least four alternatively spliced isoforms. The most highly expressed isoform (renalase1) is 342 amino acids long, and is the predominant human renalase protein detected in plasma, kidney, heart, skeletal muscle and liver. It contains a signal peptide, a flavin adenine dinucleotide (FAD)-binding region, at the extreme amino terminus, and an amine oxidase domain.
Renalase activity is markedly augmented by an increase in plasma catecholamines, suggesting that renalase plays a role in the minute to-minute regulation of blood pressure [2, 3].
Data obtained by different experimental approaches indicate that renalase deficiency, even in the absence of significant kidney disease, is associated with hypertension. Renalase gene expression, downregulated in the rat using small interfering RNAs, did not affect renal function but increased BP both at rest and during an exogenous catecholamines burst . In renalase knockout (KO) mouse, despite normal renal function, kidney histology, and plasma aldosterone levels, heart rate and BP increased both during activity and at rest .
Plasma levels are markedly reduced in patients with end stage renal disease (ESRD), suggesting that the kidney is the predominant organ which secretes renalase and regulates circulating levels. It is noteworthy that subtotal nephrectomy is associated with left ventricular hypertrophy, and interestingly this is paralleled by a significant decrease in heart hRenalase1 levels in neonatal and adult rats [3, 4].
Indeed, it was demonstrated that recombinant renalase had a protective effect on the myocardium during ischemia and decreased the myocardial infarct size by nearly one half . Finally in two rat models of renal hypoperfusion, unilateral renal artery stenosis and infarction-induced heart failure, it was shown a diminished renalase production and a concomitant increase of circulating norepinephrine suggesting that impaired synthesis of renalase by the kidney may represent a potential mechanism underlying circulating norepinephrine accumulation in heart failure [5, 6].
In humans, Zhao et al. tested for association of the RNLS gene with essential hypertension by examining several single nucleotide polymorphisms (SNPs) of RNLS in more than 2,000 individuals from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA in China).
Two SNPs (rs2576178 A > G and rs2296545 C > G) were associated with essential hypertension.
Interestingly the latter SNP leads to a conservative amino acid change (glutamic to aspartic acid at amino acid 37) which, may weaken FAD binding and affect the function of renalase. More recently, the same SNP has been associated with cardiovascular phenotypes such as cardiac hypertrophy, dysfunction and ischemia in a cohort of 590 Caucasian individuals with stable coronary artery disease (CAD) .
The aim of our study is to test if the RNLS rs2576178 A > G and rs2296545 C > G (Arg37Glu) polymorphisms is implicated in hypertension development and incidence of coronary and cerebrovascular events, acute heart failure and atrial fibrillation in a large population-based cohort study: the Malmö Diet and Cancer (MDC) study – cardiovascular arm (CVA) including more than 5,000 middle-aged subjects.