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We recently observed a significantly higher level of renalase (RNLS) in aldosterone-producing adenomas (APAs) than in the APA-adjacent adrenal glands (AAGs). RNLS is a flavin adenine dinucleotide-dependent monoamine oxidase. In this study, we investi-gated the effect of RNLS on adrenocortical aldosterone production. RNLS upregulated aldosterone production in adrenocortical cells without interfering with cell proliferation. RNLS (4 μg/ml) increased the mRNA expression of HSD3B2 (  = 0.0128) and CYP21A2 (  = 0.0013) and markedly stimulated that of CYP11B2 (  < 0.0001). Regarding the mechanism, we excluded classical calcium signalling stimulation and found that RNLS activated cAMP/PKA signalling and then upregulated the transcription factor NR4A2 and the phosphorylation of ATF/CREB family members. Immunofluorescence and immuno-precipitation results revealed that RNLS bound to the receptor PMCA4b on the cell membrane, with siPMCA4b preventing RNLS from exerting pro-aldosterone production (  = 0.0157, RNLS+siPMCA4b vs RNLS+siNC). RNLS facilitates aldosterone secretion and may emerge as a hazardous molecule for promoting aldosterone-mediated pathological conditions.

Prospective Urban and Rural Epidemiology (PURE) study is an international cohort study. Cardiovascular diseases (CVD) are a leading cause of death among worldwide. Several scales were developed to assess cardiovascular risk – one of them is SCORE system. Renalase is chemical compound which association with cardiovascular risk is likely but yet uncertain. The aim of this study was to assess the association between cardiovascular risk assessed using the SCORE system and blood renalase concentration in the Polish subpopulation of PURE study. The study group was composed of 269 participants (156 female and 113 male, 55.54 ± 7.99 years). Significant differences in blood renalase concentrations between different SCORE thresholds were found. Significant correlations between blood renalase concentrations and systolic blood pressure, as well as between blood renalase concentrations and SCORE were found. A blood renalase concentration above 84.02 ng/ml was shown to be the most accurate predictor of a SCORE < 1%. In summary, it was documented that higher blood renalase concentrations were associated with lower cardiovascular risk assessed using the SCORE system.

Renalase is a ~38 kDa flavin-adenine dinucleotide (FAD) domain-containing protein that can function as a cytokine and an anomerase. It is emerging as a novel regulator of cardiometabolic diseases. Expressed mainly in the kidneys, renalase has been reported to have a hypotensive effect and may control blood pressure through regulation of sympathetic tone. Furthermore, genetic variations in the renalase gene, such as a functional missense polymorphism (Glu37Asp), have implications in the cardiovascular and renal systems and can potentially increase the risk of cardiometabolic disorders. Research on the physiological functions and biochemical actions of renalase over the years has indicated a role for renalase as one of the key proteins involved in various disease states, such as diabetes, impaired lipid metabolism, and cancer. Recent studies have identified three transcription factors (viz., Sp1, STAT3, and ZBP89) as key positive regulators in modulating the expression of the human renalase gene. Moreover, renalase is under the post-transcriptional regulation of two microRNAs (viz., miR-29b, and miR-146a), which downregulate renalase expression. While renalase supplementation may be useful for treating hypertension, inhibition of renalase signaling may be beneficial to patients with cancerous tumors. However, more incisive investigations are required to unravel the potential therapeutic applications of renalase. Based on the literature pertaining to the function and physiology of renalase, this review attempts to consolidate and comprehend the role of renalase in regulating cardiometabolic and renal disorders.

Preeclampsia (PEC) is a complication of pregnancy associated with hypertension and the risk of eclampsia. The pathophysiology of PEC is unknown and identifying factors associated with PEC during pregnancy is crucial for placental, fetal, and maternal health. Renalase (RNLS) is an anti-inflammatory secretory flavoprotein associated with hypertension. Recent data demonstrated a correlation between maternal serum RNLS and PEC, and work from our group identified RNLS expression in the placenta. However, it remains unknown whether RNLS levels in placenta are altered by preeclampsia. Additionally, it is unclear if there is a differential effect of preterm and term PEC on RNLS. We demonstrate that serum RNLS was reduced in preterm cases of PEC. Similarly, placental RNLS was diminished in the chorion of preterm cases of PEC. However, a reduction of RNLS in the decidua was observed with all cases of PEC, while the levels of RNLS within the placental villi were similar in all cases. Overall, we demonstrate that RNLS correlates with PEC both systemically in maternal serum and locally within the placenta, with variable effects on the different layers of the placenta and more pronounced in preterm cases.

Impact of Renalase rs2296545 on Hypertension in OSA Patients

Background/Aims: Renalase, a novel flavoprotein expressed in the kidney and heart, reduces renal tubular necrosis and apoptosis, which suggests that it might protect against necrosis and/or apoptosis in myocardial ischemia reperfusion injury (MIRI). The present study thus explored the effects of renalase on Sprague-Dawley (SD) rats subjected to MIRI. Methods: We used Lentivirus-mediated RNA interference (RNAi) to inhibit the renalase gene expression in the heart tissue via pericardial cavity injection. The MIRI animal modal was established by blocking the left anterior descending artery for 45mins followed by 4h of reperfusion. Real-time PCR and western blotting were used to detect renalase expression in the heart tissue. Double staining and TUNEL were used to detect the necrosis and apoptosis in the myocardial cells, respectively. Results: All rats subjected to MIRI exhibited lower levels of renalase in the heart tissue than did the sham-operated group (P<0.05, n=6). The (RNAi) group rats exhibited lower renalase levels than did the controls and also exhibited more serious necrosis (7.12±0.56% vs. 3.32±0.93%, P<0.05, n=6) and apoptosis (151.8±8.2% vs. 66.8±6.5%, P<0.05, n=6); however, pretreatment with the recombinant renalase significantly reduced myocardial cell necrosis (1.51±0.12% vs. 4.13±0.02%, P<0.05, n=6) and apoptosis (21.3±5.0% vs. 52.6±10.4%, P<0.05, n=6) relative to the control rats. Conclusions: Exogenous recombinant renalase protein reduced myocardial cell necrosis and apoptosis. Recombinant renalase protein might be a new cardiovascular drug for ischemia/IR injury.

Obstructive sleep apnea (OSA), a condition often linked with hypertension, has an undefined relationship with renalase, a protein known for regulating blood pressure. This study aimed to investigate the relationship between serum renalase levels as well as renalase functional single nucleotide polymorphism (SNP) rs2296545 variant and hypertension in a Han Chinese OSA population. 126 subjects underwent serum renalase detection, with linear regression being performed to evaluate the relationship between serum renalase levels and OSA-related traits. Additional 4275 subjects were obtained rs2296545 genotype information by SNP microarray. And binary logistic regression was used to assess the effect of rs2296545 on hypertension risk. Molecular dynamics simulation and molecular docking were utilized to access the protein structures and the interplay between protein and catecholamines of wild-type and rs2296545 mutant renalase. The results showed that serum renalase levels were significantly higher in the severe OSA group. Further analysis showed renalase levels were positively correlated with blood pressure in the non-OSA group and negatively correlated in the severe OSA group. For rs2296545 polymorphism analysis, the hypertension risk significantly increased for the recessive model CC/GG + CG (OR = 1.211, 95% CI: 1.025–1.431) and the additive model CC/CG (OR = 1.223, 95% CI: 1.025–1.458) in the severe OSA. The rs2296545 polymorphism affected protein structure, and led to increase binding free energy, weakening interactions between renalase and catecholamines. In conclusion, serum renalase levels had independent association with blood pressure. And rs2296545 polymorphism may influence on susceptibility to hypertension by altering protein ability to bind to catecholamines, which might contribute to the intervention of hypertension in the OSA population.

Renalase, a novel flavoprotein that is mainly expressed in the kidney and heart, plays a crucial role in hypertension. Recent studies have shown that renalase is expressed at low levels in the serum of patients with heart failure, while the role of renalase and its mechanism in cardiac failure is unclear. Adult Sprague-Dawley (SD) rats were used to investigate the role and function of renalase in the pathological process of transverse aortic constriction (TAC)-induced heart failure. Renalase-human protein chip analysis showed that renalase was directly associated with P38 and extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling. We further used lentivirus-mediated RNA interference to study the role of renalase in the progression of pathological ventricular hypertrophy and found that renalase inhibition attenuated the noradrenaline-induced hypertrophic response in vitro or the pressure overload-induced hypertrophic response in vivo. Recombinant renalase protein significantly alleviated pressure overload-induced cardiac failure and was associated with P38 and ERK1/2 signaling. These findings demonstrate that renalase is a potential biomarker of hypertrophy and that exogenous recombinant renalase is a potential and novel drug for heart failure.

Cardiovascular diseases (CVDs) are one of the biggest health challenges facing health systems around the world. There are certain risk factors (CVRFs) that contribute to CVD. Risk factors associated with lifestyle such as tobacco consumption are particularly essential. Renalase is a recently discovered flavoprotein that may be involved in the progression of cardiometabolic diseases. The aim of the study was to investigate the relation between CVRFs and blood renalase concentration (BRC). The study group consisted of 96 people (51% women) who were hospitalized in the internal medicine department. CVRFs were measured using the AHA Life 7 scale. The E3109Hu ELISA kit was used to assess BRC. We found higher BRC in groups with a lower number of CVRFs (p < 0.05). We found a negative correlation between BRC and the number of CVRFs (r = −0.41). With the regression analysis, obesity, smoking, and a lack of physical activity (LoPE) were independently associated with lower blood renalase concentration. ROC analysis indicated the highest accuracy of BRC < 38.98 ng/mL in patients with ≥5 CVRFs. In conclusion, patients with a higher number of CVRFs had lower BRCs. The CVRFs particularly associated with a lower BRC were obesity, smoking, and LoPE.

Background: Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus and is associated with an increased risk of end-stage renal disease (ESRD) and cardiovascular events. Early diagnosis and monitoring of DKD are crucial for implementing appropriate interventions. This study aimed to investigate the relationship between serum renalase (RNLS) levels, DKD, and diabetic macroangiopathy in patients with type 2 diabetes mellitus (T2DM). Objectives: This study aims to evaluate the diagnostic value of serum renalase levels in DKD and diabetic macroangiopathy. Design: This is a retrospective case–control study. Methods: A total of 233 participants were recruited for the study, including 115 T2DM patients without DKD or diabetic retinopathy, and 118 T2DM patients with DKD. Serum RNLS levels were measured using an enzyme-linked immunosorbent assay. Kidney function parameters and diabetic macroangiopathy risk factors were evaluated in relation to serum RNLS levels. Results: Serum RNLS levels were significantly higher in DKD patients compared to T2DM controls (34.82 (31.68, 39.37) vs 30.52 (28.58, 33.16), p < 0.01). Multiple linear regression analysis indicated that kidney function parameters and carotid intima-media thickness were independently related to RNLS levels. The study population was divided into four groups: no DKD and no diabetic macroangiopathy, DKD without diabetic macroangiopathy, diabetic macroangiopathy without DKD, and both DKD and diabetic macroangiopathy. Analysis results showed that patients with both DKD and diabetic macroangiopathy had the highest RNLS levels. Receiver operating characteristic curve analysis demonstrated the diagnostic value of RNLS for DKD (0.76 (95% confidence interval (CI) = 0.70–0.82, p < 0.01)) and diabetic macroangiopathy (0.75 (95% CI = 0.66–0.84, p < 0.01)). Conclusion: Circulating RNLS levels were significantly increased in patients with DKD and diabetic macroangiopathy, suggesting that RNLS may serve as an early diagnostic marker.