Renalase Deficiency in Heart Failure Model of Rats—A Potential Mechanism Underlying Circulating Norepinephrine Accumulation

Abstract

BackgroundSympathetic overactivity and catecholamine accumulation are important characteristic findings in heart failure, which contribute to its pathophysiology. Here, we identify a potential mechanism underlying norepinephrine accumulation in a rat model of heart failure.Methodology/Principal FindingsInitially, we constructed a rat model of unilateral renal artery stenosis (n = 16) and found that the expression of renalase, a previously identified secreted amine oxidase, was markedly reduced in the ischemic compared to the non-ischemic kidney (protein: 0.295±0.085 versus 0.765±0.171, p<0.05). Subsequently, we utilized an isolated perfused rat kidney model to demonstrate that the clearance rate of norepinephrine decreased with reduction of perfusion flow. On the basis of these findings, we hypothesized the reduced renal blood supply which occurs in heart failure would result in impaired synthesis of renalase by the kidney and consequently reduced degradation of circulating norepinephrine. To verify this, we used a rat model of infarction-induced heart failure (n = 12 per group). In these rats, the flow velocity of renal artery, when measured at four weeks, is obviously lower in the operation group. Renal expression of renalase was reduced (protein: 0.476±0.043 for control, 0.248±0.029 for operation versus 0.636±0.151 for sham-operation) and this was associated with an increase in circulating norepinephrine (0.168±0.016 ng/mL for control, 0.203±0.019 ng/mL for operation versus 0.138±0.008 ng/mL for sham-operation).Conclusions/SignificanceRenalase expression is influenced by renal blood flow and impaired synthesis of renalase by the kidney may represent a potential mechanism underlying circulating norepinephrine accumulation in heart failure.

Levels of renalase and advanced oxidation protein products with regard to catecholamines in haemodialysed patients

“…Nevertheless, it should be emphasized that renalase is secreted not only by the kidney, but also by cardiomyocytes, liver, adipose tissue, skeletal muscles, endothelium, and by the Central Nervous System [27]. Previously, Gu et al [28] reported an increased renalase concentration in HD patients. They hypothesized that in this condition a more activated renalase was synthesized to cope with the increased NA levels.…”

Renalase — a new marker or just a bystander in cardiovascular disease: clinical and experimental data

“…In another experimental model of CKD on nephrectomised pups, Gosh et al [7] observed higher norepinephrine levels in the CKD model, suggesting its decreased metabolism. Gu et al [28] noticed lower renalase expression in the ischaemic kidney model in comparison to healthy one, suggesting that renal blood flow may affect renalase production. There are also some data concerning renalase concentration in patents with end stage renal disease.…”

“…Gu et al [28], in the study mentioned in the previous paragraph, besides observing renalase in the CKD model, also created a model of heart failure in rats through the ligation of the left anterior descending coronary artery. This group observed increasing renal renalase expression with the highest level one week after myocardial infarction [28]. There are few clinical studies considering renalase concentration in patients with heart failure.…”

Is Renalase a Novel Player in Catecholaminergic Signaling? The Mystery of the Catalytic Activity of an Intriguing New Flavoenzyme

“…First of all, as mentioned above, renalase 1 was detected in body fluids such as blood plasma and urine [1,10,29,30]. Secondly, in patients suffering from chronic kidney disease and primary glomerulonephritis, as well as in animal model of kidney failure, extracellular renalase was absent or present at lower concentrations, indicating the kidneys as the main source of the secreted protein [1,[30][31][32].…”

“…Downregulation of RNLS expression in healthy mice by antisense phosphorothioate oligonucleotides was found to produce both a rise in blood pressure and an increased sensitivity to norepinephrine injection [8,60]. In various rat models of chronic kidney disease, lower concentrations of renalase in kidneys, heart and blood were always accompanied by increased levels of epinephrine and norepinephrine in plasma and heart [30,32,61,62]. Furthermore, some of these studies together with other investigations on rodent models showed that renalase levels inversely correlate with the concentration of dopamine, which has hypotensive and cardioprotective actions at variance with other catecholamines [63], in kidneys and urine [32,64].…”