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Background: The survival of pediatric chronic kidney disease (CKD) patients has improved in recent decades due to advances in dialysis and transplantation. However, cardiovascular disease (CVD) emerges as the main cause of mortality in patients with CKD. Objectives: To estimate cardiovascular risk in children with CKD at least 1 year after kidney transplantation. In addition, the possible association of cardiovascular risk with classic biochemical markers and potential new markers of this outcome was investigated. Methods: An observational ambidirectional (retrospective capture of risk factors and prospective study of outcomes) research including 75 patients who underwent renal transplant between 2003 and 2013 with postoperative follow‐up of at least 1 year was conducted. The outcome variables adopted were the LV mass Z‐score and the presence of coronary calcification on computed tomography using calcium Agatston score. Result: Only one patient had an elevated calcium score, and three children (4%) had an LV mass Z‐score ≥ 2.0. After multivariable analysis, only gender, serum triglyceride, and serum renalase concentration remained significantly associated with LV mass. Conclusion: The low incidence of cardiovascular changes in the population studied confirms the benefit of transplantation for the cardiovascular health of children. Nevertheless, long‐term follow‐up of these patients is recommended, given the limited duration of kidney function provided by transplantation and the high likelihood of further dialysis and kidney transplants being required in these children. [ABSTRACT FROM AUTHOR]

Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development. NEW & NOTEWORTHY: Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models. [ABSTRACT FROM AUTHOR]

Hypertension and cardiovascular disease are prominent features of chronic kidney disease, and they are associated with premature mortality and progression toward end-stage kidney disease. Renalase, an enzyme secreted predominantly by the kidney and identified in 2005, seems to be one of the missing pieces in the puzzle of heart and kidney interaction in chronic kidney disease by lowering blood pressure and reducing the overactivity of sympathetic tone. This review aims to summarize evidence from clinical studies performed on subjects with CKD in order to explore the value of renalase as a marker and/or a therapeutic target in this disease. [ABSTRACT FROM AUTHOR]

Aim: The authors designed a meta-analysis to find a comprehensive result of the impact of RNLS polymorphisms on preeclampsia (PE) susceptibility. Methods: The online databases PubMed, Scopus, and Google Scholar were employed for the purpose of literature search. Data analysis was conducted using STATA (ver. 12.0) and MetaGenyo web tool. Results: The findings showed that the RNLS rs10887800 polymorphism could increase risk of PE in allelic, codominant heterozygous and dominant genetic models. In addition, the analysis indicated that the RNLS rs2576178 polymorphism was associated with higher risk of PE in allelic, codominant homozygous, dominant, and recessive models. Conclusion: The findings of meta-analysis showed that the RNLS rs10887800 and rs2576178 polymorphisms could increase risk of PE in several genetic models. Summary points Renalase is a flavoprotein that is highly expressed in the kidney and heart and possibly has a significant role in blood pressure control. The association between rs2576178 and rs10887800 polymorphisms within the RNLS gene and susceptibility to preeclampsia (PE) has been assessed in various studies; however, the results have been inconsistent. Therefore, the current meta-analysis aimed to recognize a precise consequence about the effect of rs2576178 and rs10887800 on preeclampsia risk. Pooling data from seven studies for RNLS rs10887800 and five studies for RNLS rs2576178 utilizing STATA and MetaGenyo web tool showed that both of the mentioned polymorphisms were correlated with increased risk of PE under various genetic models. The findings strengthened the relationship between RNLS gene and PE development. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the relationship between selenoprotein P, peroxiredoxin-5, renalase, total antioxidant status (TAS), mean blood pressure (mBP), and apnea-hypopnea index (AHI). Methods: The study group consisted of 112 patients hospitalized to verify the diagnosis of obstructive sleep apnea (OSA). The inclusion criteria were consent to participate in the study and age ≥ 18 years. Patients with active proliferative disease, severe systemic diseases, or mental diseases were excluded from the study. Each patient underwent full polysomnography and had blood pressure measured. Blood samples were collected and laboratory test was performed. Results: Among 112 patients enrolled, there was a statistically significant negative linear correlation between blood pressure values (sBP, dBP, mBP) and selenoprotein P, renalase, and TAS levels. Similarly, there was a negative linear correlation between AHI and selenoprotein P, renalase, and TAS levels, but none between AHI and peroxiredoxin-5. Based on the obtained regression models, higher selenoprotein P, peroxiredoxin-5, and renalase levels were independently associated with higher TAS. Lower mBP values were independently associated with the use of antihypertensive drugs, higher TAS, and younger age. Male gender, higher BMI, and higher mBP were independently associated with higher AHI. Conclusions: Higher concentrations of selenoprotein P, peroxiredoxin-5, and renalase were associated with higher TAS, which confirms their antioxidant properties. There was an indirect connection between tested antioxidants and blood pressure values. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hypertension and cardiovascular disease are prominent features of chronic kidney disease, and they are associated with premature mortality and progression toward end-stage kidney disease. Renalase, an enzyme secreted predominantly by the kidney and identified in 2005, seems to be one of the missing pieces in the puzzle of heart and kidney interaction in chronic kidney disease by lowering blood pressure and reducing the overactivity of sympathetic tone. This review aims to summarize evidence from clinical studies performed on subjects with CKD in order to explore the value of renalase as a marker and/or a therapeutic target in this disease.

Purpose: Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the sympathetic nervous system in the syndrome development, while human studies are still contradictory. The present study aims to investigate the possible influence of plasma-free metanephrine (MN), and normetanephrine (NMN), nerve growth factor (NGF), and renalase (RNL) on the hormonal and metabolic parameters in women with PCOS and healthy controls. Methods: Fifty patients with PCOS and 30 healthy women participated in the study. The plasma-free MN and NMN, NGF, RNL, anti-Mullerian hormone (AMH), gonadotropin, androgen levels, and metabolic parameters were investigated. Results: Plasma-free NMN and NGF concentrations were increased in PCOS individuals, while RNL levels were decreased compared to healthy volunteers. Increased plasma-free NMN (OR = 1.0213 [95%CI 1.0064–1.0364], p = 0.005) and NGF (OR = 1.0078 [95%CI 1.0001–1.0155], p = 0.046) but not MN or RNL levels were associated with a higher risk of PCOS after adjustment for age. Plasma-free NMN levels were positively associated with the LH (r = +0.253; p = 0.039). androstenedione (r = +0.265; p = 0.029), 17-OH progesterone (r = +0.285; p = 0.024), NGF (r = +0.320; p = 0.008), and AMH (r = +0.417; p < 0.001) concentrations of the investigated women. RNL levels were inversely related to the BMI (r = −0.245; p = 0.029), HOMA-IR (r = −0.250; p = 0.030), free testosterone (r = −0.303; p = 0.006) levels. systolic (r = −0.294; p = 0.008) and diastolic (r = −0.342; p = 0.002) blood pressure. Conclusions: Increased sympathetic noradrenergic activity and NGF synthesis might be related to the increased AMH and delta-4 androgen levels in a subgroup of PCOS patients. RNL levels might influence the metabolic status of PCOS patients. Further studies are needed to explore the significance of adrenal medullar and autonomic dysfunction for developing different PCOS phenotypes and their subsequent cardiovascular complications. [ABSTRACT FROM AUTHOR]

Objective: This study was designed to compare the serum renalase levels of polycystic ovary syndrome (PCOS) women with and without metabolic syndrome (MS) and those of healthy non-PCOS women. Materials and methods: Seventy-two patients diagnosed with PCOS and age-matched 72 healthy non-PCOS were included in the study. The PCOS group was divided into two groups as having metabolic syndrome or not. General gynecological and physical examination findings and laboratory results were recorded. Renalase levels in serum samples were determined using Enyzme-Linked ImmunoSorbent Assay method. Results: Mean serum renalase level was significantly higher in PCOS patients with MS compared with both PCOS patients without MS and healthy controls. Additionally, serum renalase correlates positively with body mass index, systolic and diastolic blood pressure, serum triglyceride and homeostasis model assessment-insulin resistance values among PCOS women. However, systolic blood pressure was found to be the only significant independent factor that can affect the serum renalase levels. A serum renalase level of 79.86 ng/L had a sensitivity of 94.7% and specificity of 46.4% in discriminating PCOS patients with metabolic syndrome from healthy women. Conclusions: Serum renalase level increases in women with PCOS in the presence of metabolic syndrome. Therefore, monitoring the serum renalase level in women with PCOS can predict the metabolic syndrome that may develop.

The cellular mechanisms and signaling network that guide the cardiac disease pathophysiology are inextricably intertwined, which explains the current scarcity of effective therapy and to date remains the greatest challenge in state-of-the-art cardiovascular medicine. Accordingly, a novel concept has emerged in which cardiomyocytes are the centerpiece of therapeutic targeting, with dysregulated mitochondria as a critical point of intervention. Mitochondrial dysfunction pluralism seeks a multi-faceted molecule, such as renalase, to simultaneously combat the pathophysiologic heterogeneity of mitochondria-induced cardiomyocyte injury. This review provides some original perspectives and, for the first time, discusses the functionality spectrum of renalase for mitochondrial dysfunction improvement within cardiac disease, including its ability to preserve mitochondrial integrity and dynamics by suppressing mitochondrial ΔΨm collapse; overall ATP content amelioration; a rise of mtDNA copy numbers; upregulation of mitochondrial genes involved in oxidative phosphorylation and cellular vitality promotion; mitochondrial fission inhibition; NAD+ supplementation; sirtuin upregulation; and anti-oxidant, anti-apoptotic, and anti-inflammatory traits. If verified that renalase, due to its multi-faceted nature, behaves like the "guardian of mitochondria" by thwarting pernicious mitochondrial dysfunction effects and exerting therapeutic potential to target mitochondrial abnormalities in failing hearts, it may provide large-scale benefits for cardiac disease patients, regardless of the underlying causes. [ABSTRACT FROM AUTHOR]

This study aimed to assess the relationship between chosen antioxidants, namely selenoprotein P (SELENOP), peroxiredoxin-5 (Prdx-5), renalase and selected cardiovascular consequences tested in ambulatory blood pressure monitoring (ABPM) and echocardiography (ECHO). In our work, cardiovascular consequences refer to higher mean blood pressure (MBP) and pulse pressure (PP) on ABPM, as well as to left atrial enlargement (LAE), left ventricular hypertrophy (LVH) and lower left ventricular ejection fraction (LVEF%) on ECHO. The study group consisted of 101 consecutive patients admitted to the Department of Internal Medicine, Occupational Diseases and Hypertension to verify the diagnosis of Obstructive Sleep Apnoea (OSA). Each patient underwent full polysomnography, blood tests, ABPM and ECHO. Both selenoprotein-P and renalase levels correlated with different ABPM and ECHO parameters. We found no correlation between the peroxiredoxin-5 level and none of the tested parameters. We point to the possible application of SELENOP plasma-level testing in the initial selection of high cardiovascular-risk patients, especially if access to more advanced examinations is limited. We further suggest SELENOP measurement as a possible indicator of patients at increased left ventricular hypertrophy risk who should be of particular interest and may benefit from ECHO testing. [ABSTRACT FROM AUTHOR]

Objective·To examine the level change of serum renalase in the patients with acute ischemic stroke (AIS), and analyze its role in evaluating disease.Methods·A total of 118 AIS patients admitted to the Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine from July 2020 to November 2021 were enrolled in the case group (AIS group). The patients were assessed for neurological deficits according to the National Institutes of Health Stroke Scale (NIHSS), and were classified as mild and moderate-severe neurological deficits. Another 133 healthy people who participated in physical examination in the physical examination center of the hospital during the same period were selected as the control group. The serum renalase levels of the two groups were detected by ELISA. Spearman's rank correlation analysis was used to evaluate the correlation between the levels of serum renalase and gender, age, fasting blood glucose, blood lipids and NIHSS scores in the patient with AIS. The predictive value of renalase expression level in AIS diagnosis was analyzed by receiver operator characteristic (ROC) curve. The factors that were statistically significant in the results of the univariate Logistic regression analysis were included in the multivariate Logistic regression model.Results·The level of serum renalase in the AIS group was 2 960.01 (1 557.99, 4 053.70) pg/mL, which was higher than 821.02 (391.29, 1 752.70) pg/mL in the control group, with a statistically significant difference (P=0.000). Spearman's rank correlation analysis showed that the levels of serum renalase in the patients with AIS were negatively correlated with the NIHSS scores (r=-0.216, P=0.019), positively correlated with the serum fasting glucose (r=0.200, P=0.030), and not significantly correlated with gender, age, low-density lipoprotein levels, total cholesterol levels, and the presence of hypertension, diabetes, or coronary heart disease. Serum renalase levels were higher in the AIS with mild neurological deficit patients than those in the moderate-severe deficit patients, and the difference was statistically significant (P=0.034). The ROC curve showed that the cut-off value of serum renalase level to diagnose AIS was 1 856.49 pg/mL, the area under the curve was 0.777±0.030 and its 95%CI was 0.718‒0.836 (P=0.000). Multivariate Logistic regression analysis showed that elevated serum renalase level [>1 856.49 pg/mL, odds ratio (OR)=6.980, P=0.000], hypertension (OR=5.382, P=0.000), and diabetes (OR=2.453, P=0.040) were risk factors for AIS.Conclusion·Serum renalase level is significantly elevated in AIS patients, and negatively correlated with NIHSS score. Serum renalase might be a potential biomarker for the auxiliary diagnosis and assessment of AIS, providing new ideas for the assessment of stroke disease progression and precise treatment.

Severe acute pancreatitis is associated with significant morbidity and mortality. Identifying factors that affect the risk of developing severe disease could influence management. Plasma levels of renalase, an anti-inflammatory secretory protein, dramatically decrease in a murine acute pancreatitis model. We assessed this response in hospitalized acute pancreatitis patients to determine if reduced plasma renalase levels occur in humans. Plasma samples were prospectively and sequentially collected from patients hospitalized for acute pancreatitis. Two forms of plasma renalase, native (no acid) and acidified, were measured by ELISA and RNLS levels were compared between healthy controls and patients with mild and severe disease (defined as APACHE-II score ≥7) using nonparametric statistical analysis. Control (33) and acute pancreatitis (mild, 230 (76.7%) and severe, 70 (23.3%) patients were studied. Acidified RNLS levels were lower in pancreatitis patients: Control: 10.1 μg/ml, Mild 5.1 μg/ml, Severe 6.0 μg/ml; p < 0.001. Native RNLS levels were increased in AP: Control: 0.4 μg/ml, Mild 0.9 μg g/ml, Severe 1.2 μg/ml p < 0.001; those with severe AP trended to have higher native RNLS levels than those with mild disease (p = 0.056). In patients with severe AP, higher APACHE-II scores at 24 h after admission correlated with lower acid-sensitive RNLS levels on admission (r = −0.31, p = 0.023). Low plasma acidified RNLS levels, and increased native RNLS levels are associated with AP. Additional studies should assess the clinical correlation between plasma RNLS levels and AP severity and outcomes. [ABSTRACT FROM AUTHOR]

The Mammalian Gene Collection Project enabled the discovery of a novel kidney enzyme, subsequently named renalase in 2005. Renalase was initially identified in proximal renal tubules, however the following research reveals its broad pattern of tissue expression. Evidence demonstrates its cytoprotective properties, establishing it as a survival element in various organ injuries (heart, kidney, liver, intestines), and as a significant anti-fibrotic factor, owing to its, in vitro and in vivo demonstrated pleiotropy to alleviate inflammation, oxidative stress, apoptosis, necrosis, and fibrotic responses. Effective anti-fibrotic therapy may seek to exploit renalase's compound effects such as: lessening of the inflammatory cell infiltrate (neutrophils and macrophages), and macrophage polarization (M1 to M2), a decrease in the proinflammatory cytokines/chemokines/reactive species/growth factor release (TNF-a, IL-6, MCP-1, MIP-2, ROS, TGF-ß1), an increase in anti-apoptotic factors (Bcl2), and prevention of caspase activation, inflammasome silencing, sirtuins activation, and mitochondrial protection, suppression of epithelial to mesenchymal transition, a decrease in the pro-fibrotic markers expression (a-SMA, collagen I, and III, TIMP-1, and fibronectin), and interference with MAPKs signaling network, most likely as a coordinator of pro-fibrotic signals. Mounting studies set the stage for renalase's pleiotropy to the level of cancer, particularly as a molecular driver for specific cancers, such as pancreatic, melanoma, renal, and breast cancer. The observation of renalase's enzymatic activities, particularly its interference with catecholamines metabolism, and regulation of plasmatic concentration, initially lead to the conclusion that renalase may significantly affect blood pressure regulation. This review provides the scientific rationale for renalase's scrutiny regarding various organ injuries, and there is great anticipation that these newly identified pathways are set to progress one-step further. Although substantial progress has been made, indicating renalase's therapeutic promise, more profound experimental work is required to resolve the accurate underlying mechanisms of renalase before any potential translation to clinical investigation. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains a serious problem in Russian and world health care due to the growing morbidity and mortality from complications of heart failure, despite the development and implementation of programs for the early detection and treatment of heart failure in asymptomatic patients. Currently, a large number of new biological markers have been studied that could serve as a laboratory tool for diagnosing and predicting the course of heart failure, but only brain natriuretic peptides have found application in real clinical practice. Renalase is a recently discovered cytokine that is synthesized by the kidneys and released into the blood. To date, seven subtypes of renalase have been found, each of which plays a different physiological role in the human body. Renalase is usually positioned as a signaling molecule that activates cytoprotective intracellular signals, leading to a decrease in blood pressure and protection of the heart muscle. The concentration of renalase freely circulating in the bloodstream of an adult is approximately 3–5 ng / ml. Currently, the level of renalase is determined by the enzyme immunoassay with a detection range of 3.12 to 200 ng / ml, while the minimum detectable concentration of the marker is less than 1.38 ng / ml. The presence of missense polymorphism of renalase is associated with myocardial dysfunction. Data from animal and human studies have shown that renalase plays a key role in the metabolism of catecholamines and in cardioprotective processes. Studies have shown the contribution of renalase to the occurrence of cardiovascular diseases: ischemic heart disease, arterial hypertension, diabetes mellitus, and aortic stenosis. Moreover, detailed protocols of multicenter prospective studies have demonstrated that functional polymorphism of the renalase gene was associated with myocardial hypertrophy in patients with aortic stenosis, hypertension, metabolic syndrome, unstable angina pectoris and stable forms of coronary artery disease, as well as in patients receiving renal replacement therapy. Based on these data and further studies, renalase has been proposed as a predictive biomarker of ischemia in patients with coronary microvascular dysfunction, as well as a predictor of clinically significant progression of chronic kidney disease in patients with cardiovascular diseases.Our review presents data on the role of renalase in heart failure. Further study of the structure and function of renalase, as well as future clinical studies, will allow determining the diagnostic, prognostic and, possibly, therapeutic significance of this biological marker in HF and other cardiovascular diseases.

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.

IntroductionCKD-induced pathological cardiac remodeling is characterized by myocardial hypertrophy and cardiac fibrosis. The available therapeutic options are limited, it is thus urgently needed to identify novel therapeutic targets. Renalase (RNLS) is a newly discovered protein secreted by the kidney and was found beneficial in many renal diseases. But whether it exerts protective effects on cardiac remodeling in CKD remains unclear.MethodsRNLS knockout (KO) and wild-type (WT) mice were both used to build CKD models and the adeno-associated virus (AAV9) system was used to overexpress RNLS cardiac specifically. Echocardiography was performed to detect cardiac structural changes every 6 weeks until 18 weeks post-surgery. High throughput sequencing was performed to understand the underlying mechanisms and the effects of RNLS on cardiac fibroblasts were validated in vitro.ResultsKnockout of RNLS aggravated cardiac remodeling in CKD, while RNLS cardiac-specific overexpression significantly reduced left ventricular hypertrophy and cardiac fibrosis induced by CKD. The following RNA-sequencing analysis revealed that RNLS significantly downregulated the extracellular matrix (ECM) receptor interaction pathway, ECM organization, and several ECM-related proteins. GSEA results showed RNLS significantly downregulated several profibrotic biological processes of cardiac fibroblasts which were upregulated by CKD, including fibroblast proliferation, leukocyte migration, antigen presentation, cytokine production, and epithelial-mesenchymal transition (EMT). In vitro, we validated that RNLS reduced the primary cardiac fibroblast proliferation and α-SMA expression stimulated by TGF-β.ConclusionIn this study, we examined the cardioprotective role of RNLS in CKD-induced cardiac remodeling. RNLS may be a potential therapeutic factor that exerts an anti-fibrotic effect in pathological cardiac remodeling.

Objective: Left ventricular hypertrophy is the most commonly studied index for hypertension related target organ damage due to the wide usage of echocardiography. Renalase is a monoamine oxidase, mainly produced by the kidneys, regulating blood pressure by reducing catecholamines and acting on cardiovascular functions. In this study, the relationship between serum renalase level and hypertensive cardiac changes in children with essential hypertension was compared with the healthy control group. Material and Methods: A total of 60 hypertensive children (female/male 20/40) aged between 4-18 years (mean 15.1±1.9 years) were included in the study. Twenty healthy children with normal body mass index (4-18, mean14.2±1.3 years) and similar gender (female/ male 10/10) formed the control group. In 30 of hypertensive children (female/male: 9/21), echocardiography showed left ventricular hypertrophy. Echocardiographic findings of 30 remaining hypertensive patients (female/male: 11/19) were normal. A venous blood sample was collected from the hypertensive groups for biochemical examinations and renalase level. Urine samples and 24-hour urine samples were collected. 24-hour ambulatory blood pressure monitoring (ABPM) was used to measure blood pressure of hypertensive groups. The cardiac evaluation of hypertensive groups was performed using M-mode echocardiography. Results: The body mass index was significantly higher in hypertensive groups than the group with normal blood pressure (p <0.05). In comparison of hypertensive groups, no significant difference was found in terms of body mass index. All day systolic, diastolic; night systolic, diastolic, and daytime systolic blood pressure loads were significantly higher in hypertensive left-ventricular hypertrophic group than hypertensive non-hypertrophic group (p <0.05). Left ventricular mass index in M-mode echocardiography, revealed 39.7 g/m² in the left ventricular hypertrophic group and 27.9 g/m² in the hypertensive non-hypertrophic group (p <0.05). When the relationship between blood pressure loads and left ventricular mass index was compared between the groups, a significant correlation was found between daytime systolic blood pressure load and increased left ventricular mass index (p <0.05). Renalase level was significantly lower in hypertensive groups compared to normotensive group (p <0.05). There is a relationship between renalase deficiency and increased left ventricular mass index. Conclusion: There is a correlation between renalase deficiency and increased left ventricular mass index. We believe that utilization of low renalase levels as an early marker may be a useful and valuable parameter for determining the patients at risk for left ventricular hypertrophy and long-term complications of hypertension [ABSTRACT FROM AUTHOR]

Background. Renalase is an enzyme secreted by the kidneys, which takes part in the regulation of arterial pressure, myocardial contractility and modulation of vascular resistance, but its effect on renalase levels in newborns has not been studied yet. The levels of advanced oxidation protein products (AOPPs) were also evaluated as a marker of oxidative stress. Objectives. This study examined whether renalase and AOPP levels are different in the cord blood of newborns exposed to gestational hypertension (HT). The association of both factors with perinatal and anthropometric data among the studied patients was assessed. Materials and methods. The study included 89 newborns: 30 newborns from the study group, whose mothers were diagnosed with gestational HT, and 59 newborns born from normal pregnancies, who formed the control group. Anthropometric measurements and perinatal data in newborns in both groups were recorded. Results. A significantly lower (p < 0.001) concentration of renalase was found in the study group (median (Q1-Q3): 23.96 µg/mL (20.63-26.91 µg/mL)) as compared to the control group (median (Q1-Q3): 37.54 µg/mL (33.78-40.02 µg/mL)). In case of AOPPs, a significantly higher (p < 0.001) concentration of AOPPs was observed in the study group (median (Q1-Q3): 131.65 µmol/L (113.80-146.10 µmol/L)) than in the controls (median (Q1-Q3): 93.70 µmol/L (87.10-111.20 µmol/L)). Conclusions. A significant difference between renalase and AOPP concentrations between the study and control groups has been demonstrated. Both factors may influence anthropometric and perinatal outcomes of newborns. [ABSTRACT FROM AUTHOR]

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., (© The Author(s), 2024.)

The cellular mechanisms and signaling network that guide the cardiac disease pathophysiology are inextricably intertwined, which explains the current scarcity of effective therapy and to date remains the greatest challenge in state-of-the-art cardiovascular medicine. Accordingly, a novel concept has emerged in which cardiomyocytes are the centerpiece of therapeutic targeting, with dysregulated mitochondria as a critical point of intervention. Mitochondrial dysfunction pluralism seeks a multi-faceted molecule, such as renalase, to simultaneously combat the pathophysiologic heterogeneity of mitochondria-induced cardiomyocyte injury. This review provides some original perspectives and, for the first time, discusses the functionality spectrum of renalase for mitochondrial dysfunction improvement within cardiac disease, including its ability to preserve mitochondrial integrity and dynamics by suppressing mitochondrial ΔΨm collapse; overall ATP content amelioration; a rise of mtDNA copy numbers; upregulation of mitochondrial genes involved in oxidative phosphorylation and cellular vitality promotion; mitochondrial fission inhibition; NAD+ supplementation; sirtuin upregulation; and anti-oxidant, anti-apoptotic, and anti-inflammatory traits. If verified that renalase, due to its multi-faceted nature, behaves like the “guardian of mitochondria” by thwarting pernicious mitochondrial dysfunction effects and exerting therapeutic potential to target mitochondrial abnormalities in failing hearts, it may provide large-scale benefits for cardiac disease patients, regardless of the underlying causes.

We aimed to examine the effects of aerobic exercise training on renal function in spontaneously hypertensive rats (SHR) and elucidate their possible mechanisms. Adult male SHR and age-matched Wistar-Kyoto rats (WKY) were divided into four groups: WKY sedentary group, SHR sedentary group, low-intensity training group, and medium-intensity training group. Using molecular and biochemical approaches, we investigated the effects of 14-week training on renalase (RNLS) protein levels, renal function, and apoptosis and oxidative stress modulators in kidney tissues. In vitro, angiotensin II (Ang II)-induced human kidney proximal epithelial cells (HK-2) were treated with RNLS, and changes in apoptosis and oxidative stress levels were observed. Our results show that moderate training improved renal function decline in SHR. In addition, aerobic exercise therapy significantly increased levels of RNLS in the renal medulla of SHR. We observed in vitro that RNLS significantly inhibited the increase of Ang II-inducedapoptosis and oxidative stress levels in HK-2. In conclusion, aerobic exercise training effectively improved renal function in SHR by promoting RNLS expression in the renal medulla. These results explain the possible mechanism in which exercise improves renal injury in hypertensive patients and suggest RNLS as a novel therapy for kidney injury patients.

This study aimed to assess the relationship between chosen antioxidants, namely selenoprotein P (SELENOP), peroxiredoxin-5 (Prdx-5), renalase and selected cardiovascular consequences tested in ambulatory blood pressure monitoring (ABPM) and echocardiography (ECHO). In our work, cardiovascular consequences refer to higher mean blood pressure (MBP) and pulse pressure (PP) on ABPM, as well as to left atrial enlargement (LAE), left ventricular hypertrophy (LVH) and lower left ventricular ejection fraction (LVEF%) on ECHO. The study group consisted of 101 consecutive patients admitted to the Department of Internal Medicine, Occupational Diseases and Hypertension to verify the diagnosis of Obstructive Sleep Apnoea (OSA). Each patient underwent full polysomnography, blood tests, ABPM and ECHO. Both selenoprotein-P and renalase levels correlated with different ABPM and ECHO parameters. We found no correlation between the peroxiredoxin-5 level and none of the tested parameters. We point to the possible application of SELENOP plasma-level testing in the initial selection of high cardiovascular-risk patients, especially if access to more advanced examinations is limited. We further suggest SELENOP measurement as a possible indicator of patients at increased left ventricular hypertrophy risk who should be of particular interest and may benefit from ECHO testing.

Although programmed cell death protein 1 (PD-1) inhibitors have revolutionised treatment for advanced melanoma, not all patients respond. We previously showed that inhibition of the flavoprotein renalase (RNLS) in preclinical melanoma models decreases tumour growth. We hypothesised that RNLS inhibition promotes tumour rejection by effects on the tumour microenvironment (TME). We used two distinct murine melanoma models, studied in RNLS knockout (KO) or wild-type (WT) mice. WT mice were treated with the anti-RNLS antibody, m28, with or without anti-PD-1. 10X single-cell RNA-sequencing was used to identify transcriptional differences between treatment groups, and tumour cell content was interrogated by flow cytometry. Samples from patients treated with immunotherapy were examined for RNLS expression by quantitative immunofluorescence. RNLS KO mice injected with wild-type melanoma cells reject their tumours, supporting the importance of RNLS in cells in the TME. This effect was blunted by anti-cluster of differentiation 3. However, MØ-specific RNLS ablation was insufficient to abrogate tumour formation. Anti-RNLS antibody treatment of melanoma-bearing mice resulted in enhanced T cell infiltration and activation and resulted in immune memory on rechallenging mice with injection of melanoma cells. At the single-cell level, treatment with anti-RNLS antibodies resulted in increased tumour density of MØ, neutrophils and lymphocytes and increased expression of IFNγ and granzyme B in natural killer cells and T cells. Intratumoural Forkhead Box P3 + CD4 cells were decreased. In two distinct murine melanoma models, we showed that melanoma-bearing mice treated with anti-RNLS antibodies plus anti-PD-1 had superior tumour shrinkage and survival than with either treatment alone. Importantly, in pretreatment samples from patients treated with PD-1 inhibitors, high RNLS expression was associated with decreased survival (log-rank P = 0.006), independent of other prognostic variables. RNLS KO results in melanoma tumour regression in a T-cell-dependent fashion. Anti-RNLS antibodies enhance anti-PD-1 activity in two distinct aggressive murine melanoma models resistant to PD-1 inhibitors, supporting the development of anti-RNLS antibodies with PD-1 inhibitors as a novel approach for melanomas poorly responsive to anti-PD-1. • Renalase (RNLS) knockout in immune cells substantially inhibits tumour growth. • Anti-RNLS antibodies enhance effects of anti-programmed cell death protein 1 (PD-1) in melanoma-bearing mice. • T cells (but not MØ) are required for anti-RNLS effects on tumours. • Immunotherapy-treated patients with melanoma with high tumour RNLS have worse survival. • Anti-RNLS antibodies might have therapeutic value in anti-PD-1–resistant melanomas. [ABSTRACT FROM AUTHOR]

Despite advances in obstetric medicine, the pathogenesis of preeclampsia (PE) remains poorly understood. It has been suggested that PE results from a state of sympathetic hyperactivity with circulating catecholamines increased in this condition. A new enzyme, called Renalase, has recently been identified exhibiting activity on the metabolism of catecholamine and blood pressure reduction when administered in vivo. Thus, this study was conducted to evaluate the possible association between the presence of the Renalase gene (RNLS) (rs10887800) polymorphism and mechanisms that control the pathogenesis of PE. This was a cross-sectional, quantitative, case-control study with 94 pregnant women with PE (cases) and 97 normotensive pregnant women (controls). A standardized form was used to collect demographic and clinical data; oral scraping samples were collected, and DNA extraction and subsequent real-time polymerase chain reaction (PCR) were conducted to evaluate the presence of rs10887800. In terms of genotypic distribution and frequency of alleles, no significant association was observed between the rs10887800 polymorphism and development of PE, or with its severe form. However, the GG genotype was associated with a trend of higher risk of PE (GG vs. AG + AA: OR = 2.16, 0.97-4.86, p = 0.05). Hence, the rs10887800 polymorphism could not be determined as a predisposing factor for PE susceptibility or severity in the studied population. [ABSTRACT FROM AUTHOR]

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Cardiac fibrosis represents a redundant accumulation of extracellular matrix proteins, resulting from a cascade of pathophysiological events involved in an ineffective healing response, that eventually leads to heart failure. The pathophysiology of cardiac fibrosis involves various cellular effectors (neutrophils, macrophages, cardiomyocytes, fibroblasts), up-regulation of profibrotic mediators (cytokines, chemokines, and growth factors), and processes where epithelial and endothelial cells undergo mesenchymal transition. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. The most effective anti-fibrotic strategy will have to incorporate the specific targeting of the diverse cells, pathways, and their cross-talk in the pathogenesis of cardiac fibroproliferation. Additionally, renalase, a novel protein secreted by the kidneys, is identified. Evidence demonstrates its cytoprotective properties, establishing it as a survival element in various organ injuries (heart, kidney, liver, intestines), and as a significant anti-fibrotic factor, owing to its, in vitro and in vivo demonstrated pleiotropy to alleviate inflammation, oxidative stress, apoptosis, necrosis, and fibrotic responses. Effective anti-fibrotic therapy may seek to exploit renalase’s compound effects such as: lessening of the inflammatory cell infiltrate (neutrophils and macrophages), and macrophage polarization (M1 to M2), a decrease in the proinflammatory cytokines/chemokines/reactive species/growth factor release (TNF-α, IL-6, MCP-1, MIP-2, ROS, TGF-β1), an increase in anti-apoptotic factors (Bcl2), and prevention of caspase activation, inflammasome silencing, sirtuins (1 and 3) activation, and mitochondrial protection, suppression of epithelial to mesenchymal transition, a decrease in the pro-fibrotic markers expression (’α-SMA, collagen I, and III, TIMP-1, and fibronectin), and interference with MAPKs signaling network, most likely as a coordinator of pro-fibrotic signals. This review provides the scientific rationale for renalase’s scrutiny regarding cardiac fibrosis, and there is great anticipation that these newly identified pathways are set to progress one step further. Although substantial progress has been made, indicating renalase’s therapeutic promise, more profound experimental work is required to resolve the accurate underlying mechanisms of renalase, concerning cardiac fibrosis, before any potential translation to clinical investigation.

Renalase was first described in 2005 and since then it became an object of scientific interest because of its proposed ability to catalyse circulating neurotransmitters and its promising antihypertensive effects. However, further research on the enzymatic activity of renalase did not confirm these initial findings and yielded that renalase serves to oxidize isomeric forms of β‐NAD(P)H and recycle them by forming β‐NAD(P)+. Moreover, in contrast to initial assumptions, it is indicated that renalase's enzymatic activity is confined to the cell and that extracellular renalase loses its enzymatic properties. These new reports led scientists to question as to whether renalase, as an enzyme, still has the potential to influence various systemic physiological responses (e.g. blood pressure). It was also put into question whether many physiological discoveries published based on the notion that renalase is secreted into the blood and acts by oxidation of catecholamines can still be considered valid. In this article, we attempt to review the literature to confront these doubts and find further possible directions of research on the importance of renalase. Our aim was to evaluate recent reports of non‐enzymatic activity for renalase. [ABSTRACT FROM AUTHOR]

ObjectiveRenalase, a novel secretory flavoprotein with amine oxidase activity, is secreted into the blood by the kidneys and is hypothesized to participate in blood pressure (BP) regulation. We investigated the associations of renalase with BP and the risk of hypertension by examining renalase single nucleopeptide polymorphism (SNPs), serum renalase levels, and renal expression of renalase in humans.Methods① Subjects (n = 514) from the original Baoji Salt-Sensitive Study cohort were genotyped to investigate the association of renalase SNPs with longitudinal BP changes and the risk of hypertension during 14 years of follow-up. ② Two thousand three hundred and ninety two participants from the Hanzhong Adolescent Hypertension Study cohort were used to examine the association of serum renalase levels with hypertension. Renalase expression in renal biopsy specimens from 193 patients were measured by immunohistochemistry. ③ Renalase expression was compared in hypertensive vs. normotensive patients.Results① SNP rs7922058 was associated with 14-year change in systolic BP, and rs10887800, rs796945, rs1935582, rs2296545, and rs2576178 were significantly associated with 14-year change in diastolic BP while rs1935582 and rs2576178 were associated with mean arterial pressure change over 14 years. In addition, SNPs rs796945, rs1935582, and rs2576178 were significantly associated with hypertension incidence. Gene-based analysis found that renalase gene was significantly associated with hypertension incidence over 14-year follow-up after adjustment for multiple measurements. ② Hypertensive subjects had higher serum renalase levels than normotensive subjects (27.2 ± 0.4 vs. 25.1 ± 0.2 μg/mL). Serum renalase levels and BPs showed a linear correlation. In addition, serum renalase was significantly associated with the risk of hypertension [OR = 1.018 (1.006–1.030)]. ③ The expression of renalase in human renal biopsy specimens significantly decreased in hypertensive patients compared to non-hypertensive patients (0.030 ± 0.001 vs. 0.038 ± 0.004).ConclusionsThese findings indicate that renalase may play an important role in BP progression and development of hypertension.

Renalase (RNLS) is a recently discovered protein that plays an important role in the regulation of blood pressure by acting inside and outside cells. Intracellular RNLS is a FAD-dependent oxidoreductase that oxidizes isomeric forms of β-NAD(P)H. Extracellular renalase lacking its N-terminal peptide and cofactor FAD exerts various protective effects via non-catalytic mechanisms. Certain experimental evidence exists in the literature that the RP220 peptide (a 20-mer peptide corresponding to the amino acid sequence RNLS 220-239) reproduces a number of non-catalytic effects of this protein, acting on receptor proteins of the plasma membrane. The possibility of interaction of this peptide with intracellular proteins has not been studied. Taking into consideration the known role of RNLS as a possible antihypertensive factor, the aim of this study was to perform proteomic profiling of the kidneys of normotensive and hypertensive rats using RP220 as an affinity ligand. Proteomic (semi-quantitative) identification revealed changes in the relative content of about 200 individual proteins in the kidneys of hypertensive rats bound to the affinity sorbent as compared to the kidneys of normotensive animals. Increased binding of SHR renal proteins to RP220 over the normotensive control was found for proteins involved in the development of cardiovascular pathology. Decreased binding of the kidney proteins from hypertensive animals to RP220 was noted for components of the ubiquitin-proteasome system, ribosomes, and cytoskeleton.

Preeclampsia (PE) is one of the major contributors to maternal and fetal mortality worldwide. Many host-related biomolecules regulate the pathophysiology of PE. The current study aims to examine the role of the renalase in PE manifestations. A total of 384 Chinese women consisting of subjects with normotensive pregnancy (n = 105), women with PE (n = 121), and healthy women (n = 158) were included in the study. Serum renalase level was measured in all subjects by ELISA. Renalase gene polymorphisms (rs10887800, rs2576178, and rs2296545) were genotyped by PCR-RFLP. The pregnant women had elevated renalase levels compared to healthy controls and subjects with PE. Renalase level was negatively correlated with systolic and diastolic blood pressure. Interestingly, renalase was positively correlated with the glomerular filtration rate. Prevalence of homozygous mutant (GG) and minor allele (G) for rs10887800 and rs2576178 renalase gene polymorphisms were significantly higher in PE patients compared to normotensive pregnant women and healthy controls. Furthermore, an association of G-G-C haplotype with susceptibility to PE was also noticed. A low level of renalase may be associated with an increased risk of PE during pregnancy. Renalase gene polymorphisms (rs10887800 and rs2576178) are correlated with serum renalase and are associated with predisposition to PE development in the Chinese cohort. [ABSTRACT FROM AUTHOR]

Objective: Hypertension is one of the cardiovascular diseases that causes the most mortality, and 95% of the causes are unknown. The aim of the study was to examine the possible correlation of nesfatin-1 levels, adropin levels, claudin-2 immunoreactivity (claudin-2 expression in the renal proximal tubule), and renalase immunoreactivity (renalase expression in the renal proximal tubule) with arterial blood pressure, kidney function, and kidney damage., Methods: Adult male Sprague Dawley rats were divided into control and hypertension groups (8 per group). Angiotensin II vehicle was given to the control group and angiotensin II (0.7 mg/kg/day) to the hypertension group, both via an osmotic mini pump for 7 days. The animals blood pressures were measured by tail cuff plethysmography on days 1, 3, 5, and 7. On day 7, 24-hour urine, blood, and tissues were collected from the rats., Results: In the hypertension group compared with the control group, there was an increase in systolic blood pressure levels after day 1. While claudin-2 immunoreactivity was reduced in the kidneys, renalase immunoreactivity was increased. There was a decrease in creatinine clearance and an increase in fractional potassium excretion (P < .05)., Conclusion: Our results showed that claudin-2 and renalase are associated with renal glomerular and tubular dysfunction and may play discrete roles in the pathogenesis of hypertension. We believe that these potential roles warrant further investigation.

The aim of our study was to evaluate the influence of asymptomatic infection and the occurrence of symptomatic COVID-19 on specific biochemical, renal, and immune parameters—renalase, neutrophil gelatinase-associated lipocalin (NGAL) cystatin C (CysC), and creatinine—and their weekly fluctuations during a one-month observation period in COVID-19 patients admitted to hospital. The study involved 86 individuals: 30 patients with diagnosed COVID-19, 28 people with asymptomatic infection confirmed with IgG antibodies—the IG(+) group—and 28 individuals without any (IgG, IgE) anti-SARS-CoV-2 antibodies—the IG(−) group. In the COVID-19 group, blood was drawn four times: (1) on day 0/1 after admission to hospital (C1 group), (2) 7 days later (C7 group), (3) 14 days later (C14 group), and (4) 28 days later (C28 group). In the IG(−) and IG(+) groups, blood was drawn once. There were no significant differences in creatinine, Cys C, and uric acid between any of the analyzed groups. NGAL levels were significantly higher in IG(+) and at all time-points in the COVID-19 groups than in controls. A similar observation was made for renalase at the C7, C14, and C28 time-points. Plasma renalase, NGAL, and CysC are unrelated to kidney function in non-critically ill COVID-19 patients and those with asymptomatic infection. Renalase and NGAL are most likely related to the activation of the immune system rather than kidney function. Asymptomatic SARS-CoV-2 infection causes a rise in plasma NGAL levels similar to those observed in symptomatic COVID-19 patients. Therefore, more attention should be paid to tracking and monitoring the health of these people.

Renalase (RNLS) is a secretory protein discovered in 2005. It plays an important role in the regulation of blood pressure. Studies by two independent laboratories have shown that administration of purified recombinant RNLS reduced blood pressure in experimental animals. However, the mechanisms of the antihypertensive effect of RNLS still remain unclear, especially in the context of the shift in the catalytic paradigm of this protein. In addition, there is growing evidence that endogenous plasma/serum RNLS, detected by enzyme immunoassay, is not an intact protein secreted into the extracellular space, and exogenous recombinant RNLS is effectively cleaved during short-term incubation with human plasma samples. This suggests that the antihypertensive effect of RNLS may be due to peptides formed during proteolytic processing. Based on the results of a bioinformatics analysis of potential RNLS cleavage sites (Fedchenko et al., Medical Hypotheses, 2022; DOI: 10.1016/j.mehy.2022.110895), a number of short peptides have been identified in the RNLS sequence that show similarity to fragments of known peptide inhibitors of angiotensin-converting enzyme. Some of them were found as a part of larger RNLS peptides, formed during RNLS cleavage by chymotrypsin and, and to a lesser extent, by trypsin.

Renalase, a key mediator of cross-talk between kidneys and sympathetic nervous system, exerts protective roles in various cardiovascular/renal disease states. However, molecular mechanisms underpinning renalase gene expression remain incompletely understood. Here, we sought to identify the key molecular regulators of renalase under basal/catecholamine-excess conditions. Identification of the core promoter domain of renalase was carried out by promoter-reporter assays in N2a/HEK-293/H9c2 cells. Computational analysis of the renalase core promoter domain, over-expression of cyclic-AMP-response-element-binding-protein (CREB)/dominant negative mutant of CREB, ChIP assays were performed to determine the role of CREB in transcription regulation. Role of the miR-29b-mediated-suppression of renalase was validated in-vivo by using locked-nucleic-acid-inhibitors of miR-29. qRT-PCR and Western-blot analyses measured the expression of renalase, CREB, miR-29b and normalization controls in cell lysates/ tissue samples under basal/epinephrine-treated conditions. CREB, a downstream effector in epinephrine signaling, activated renalase expression via its binding to the renalase-promoter. Physiological doses of epinephrine and isoproterenol enhanced renalase-promoter activity and endogenous renalase protein level while propranolol diminished the promoter activity and endogenous renalase protein level indicating a potential role of beta-adrenergic receptor in renalase gene regulation. Multiple animal models (acute exercise, genetically hypertensive/stroke-prone mice/rat) displayed directionally-concordant expression of CREB and renalase. Administration of miR-29b inhibitor in mice upregulated endogenous renalase expression. Moreover, epinephrine treatment down-regulated miR-29b promoter-activity/transcript levels. This study provides evidence for renalase gene regulation by concomitant transcriptional activation via CREB and post-transcriptional attenuation via miR-29b under excess epinephrine conditions. These findings have implications for disease states with dysregulated catecholamines. [Display omitted] • Regulation of renalase gene, a novel cardiovascular modulator, is partially understood. • CREB governs renalase expression under basal and epinephrine-induced conditions. • miR-29b modulates renalase expression in vivo. • Epinephrine down-regulates miR-29b and activates renalase expression. • CREB-miR-29b cross-talk modulates renalase expression in excess catecholamine conditions. [ABSTRACT FROM AUTHOR]

Objective: This study was designed to compare the serum renalase levels of polycystic ovary syndrome (PCOS) women with and without metabolic syndrome (MS) and those of healthy non-PCOS women., Materials and Methods: Seventy-two patients diagnosed with PCOS and age-matched 72 healthy non-PCOS were included in the study. The PCOS group was divided into two groups as having metabolic syndrome or not. General gynecological and physical examination findings and laboratory results were recorded. Renalase levels in serum samples were determined using Enyzme-Linked ImmunoSorbent Assay method., Results: Mean serum renalase level was significantly higher in PCOS patients with MS compared with both PCOS patients without MS and healthy controls. Additionally, serum renalase correlates positively with body mass index, systolic and diastolic blood pressure, serum triglyceride and homeostasis model assessment-insulin resistance values among PCOS women. However, systolic blood pressure was found to be the only significant independent factor that can affect the serum renalase levels. A serum renalase level of 79.86 ng/L had a sensitivity of 94.7% and specificity of 46.4% in discriminating PCOS patients with metabolic syndrome from healthy women., Conclusions: Serum renalase level increases in women with PCOS in the presence of metabolic syndrome. Therefore, monitoring the serum renalase level in women with PCOS can predict the metabolic syndrome that may develop., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest. The authors declare no financial disclosure. All authors read and approved the final manuscript. This manuscript is not under consideration for publication anywhere else., (Copyright © 2023. Published by Elsevier B.V.)

Background: Treating renal fibrosis is crucial to delaying chronic kidney disease. The glycogen synthase kinase-3β (GSK-3β)/Snail pathway regulates renal fibrosis and Renalase can ameliorate renal interstitial fibrosis. However, it is not clear whether GSK-3β/Snail signaling affects Renalase action. Here, we explored the role and mechanism of GSK-3β/Snail in the anti-fibrosis action of Renalase. Materials and methods: We used mice with complete unilateral ureteral obstruction (UUO) and human proximal renal tubular epithelial (HK-2) cells with transforming growth factor-β1 (TGF-β1)-induced fibrosis to explore the role and regulatory mechanism of the GSK-3β/Snail pathway in the amelioration of renal fibrosis by Renalase. Results: In UUO mice and TGF-β1-induced fibrotic HK-2 cells, the expression of p-GSK-3β-Tyr216/p-GSK-3β-Ser9, GSK-3β and Snail was significantly increased, and endoplasmic reticulum (ER) stress was activated. After Renalase supplementation, fibrosis was alleviated, ER stress was inhibited and p-GSK-3β-Tyr216/p-GSK-3β-Ser9, GSK-3β and Snail were significantly down-regulated. The amelioration of renal fibrosis by Renalase and its inhibitory effect on GSK-3β/Snail were reversed by an ER stress agonist. Furthermore, when an adeno-associated virus or plasmid was used to overexpress GSK-3β, the effect of Renalase on delaying renal fibrosis was counteracted, although ER stress markers did not change. Conclusion: Renalase prevents renal fibrosis by down-regulating GSK-3β/Snail signaling through inhibition of ER stress. Exogenous Renalase may be an effective method of slowing or stopping chronic kidney disease progression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background/objectives: Severe acute pancreatitis is associated with significant morbidity and mortality. Identifying factors that affect the risk of developing severe disease could influence management. Plasma levels of renalase, an anti-inflammatory secretory protein, dramatically decrease in a murine acute pancreatitis model. We assessed this response in hospitalized acute pancreatitis patients to determine if reduced plasma renalase levels occur in humans., Methods: Plasma samples were prospectively and sequentially collected from patients hospitalized for acute pancreatitis. Two forms of plasma renalase, native (no acid) and acidified, were measured by ELISA and RNLS levels were compared between healthy controls and patients with mild and severe disease (defined as APACHE-II score ≥7) using nonparametric statistical analysis., Results: Control (33) and acute pancreatitis (mild, 230 (76.7%) and severe, 70 (23.3%) patients were studied. Acidified RNLS levels were lower in pancreatitis patients: Control: 10.1 μg/ml, Mild 5.1 μg/ml, Severe 6.0 μg/ml; p < 0.001. Native RNLS levels were increased in AP: Control: 0.4 μg/ml, Mild 0.9 μg g/ml, Severe 1.2 μg/ml p < 0.001; those with severe AP trended to have higher native RNLS levels than those with mild disease (p = 0.056). In patients with severe AP, higher APACHE-II scores at 24 h after admission correlated with lower acid-sensitive RNLS levels on admission (r = -0.31, p = 0.023)., Conclusion: Low plasma acidified RNLS levels, and increased native RNLS levels are associated with AP. Additional studies should assess the clinical correlation between plasma RNLS levels and AP severity and outcomes., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction: CKD-induced pathological cardiac remodeling is characterized by myocardial hypertrophy and cardiac fibrosis. The available therapeutic options are limited, it is thus urgently needed to identify novel therapeutic targets. Renalase (RNLS) is a newly discovered protein secreted by the kidney and was found beneficial in many renal diseases. But whether it exerts protective effects on cardiac remodeling in CKD remains unclear., Methods: RNLS knockout (KO) and wild-type (WT) mice were both used to build CKD models and the adeno-associated virus (AAV9) system was used to overexpress RNLS cardiac specifically. Echocardiography was performed to detect cardiac structural changes every 6 weeks until 18 weeks post-surgery. High throughput sequencing was performed to understand the underlying mechanisms and the effects of RNLS on cardiac fibroblasts were validated in vitro ., Results: Knockout of RNLS aggravated cardiac remodeling in CKD, while RNLS cardiac-specific overexpression significantly reduced left ventricular hypertrophy and cardiac fibrosis induced by CKD. The following RNA-sequencing analysis revealed that RNLS significantly downregulated the extracellular matrix (ECM) receptor interaction pathway, ECM organization, and several ECM-related proteins. GSEA results showed RNLS significantly downregulated several profibrotic biological processes of cardiac fibroblasts which were upregulated by CKD, including fibroblast proliferation, leukocyte migration, antigen presentation, cytokine production, and epithelial-mesenchymal transition (EMT). In vitro , we validated that RNLS reduced the primary cardiac fibroblast proliferation and α-SMA expression stimulated by TGF-β., Conclusion: In this study, we examined the cardioprotective role of RNLS in CKD-induced cardiac remodeling. RNLS may be a potential therapeutic factor that exerts an anti-fibrotic effect in pathological cardiac remodeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Bai, Wen, Zhang, Gu, Wang, Yin and Wang.)

Renalase (RNLS) is an intriguing protein, which plays different roles inside and outside cells. Intracellular RNLS is a FAD-dependent oxidoreductase (EC 1.6.3.5), while extracellular RNLS lacks its N-terminal peptide, FAD cofactor, and exhibits various protective effects in a non-catalytic manner. Numerous ELISA-based studies revealed altered RNLS levels in blood of patients with various chronic renal diseases (CRD) and cardiovascular diseases (CVD), including hypertension. However, our mass spectrometry data (Medvedev et al., Int. J. Cardiol., 2020, 307: 179) indicate the lack of an internal fragment located in the central part of RNLS. This means that plasma/serum RNLS is not an intact protein secreted into extracellular space. Our hypothesis is that reaching systemic circulation RNLS undergoes proteolytic cleavage by plasma proteases. In order to verify this hypothesis we incubated purified human recombinant RNLS with plasma samples from healthy volunteers and evaluated the remaining full-length RNLS by Western blot with polyclonal antibodies. These experiments revealed a significant decrease of the full-length RNLS. In an attempt to find putative enzymes responsible for RNLS cleavage in human blood, we have analyzed possible involvement of proteases in the cleavage of the RNLS amino acid sequence. The bioinformatics analysis performed by means of PeptideCutter and Procleave programs revealed several candidates that would be able to cleave RNLS in humans as well as blood proteases unable to cleave RNLS (e.g. thrombin). Direct experiments with purified enzymes have shown that in addition to trypsin, the classical cutting protease used in proteomics, only chymotrypsin effectively cleaved RNLS, while thrombin was ineffective. Since chymotrypsin is a protease normally acting in the small intestine we hypothesize that related chymotrypsin like enzymes secreted into blood can perform initial cleavage of blood RNLS with subsequent formation of RNLS-derived peptides possessing various biological effects. An understanding of the fact that blood RNLS can be effectively cleaved by some plasma proteases would help to asses actual levels of this potential biomarker in norm and disease. [ABSTRACT FROM AUTHOR]