The early diagnostic value of serum renalase level in diabetic kidney disease and diabetic macroangiopathy: a retrospective case-control study.

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.

Renalase rs2296545 variant improve hypertension susceptibility by modifying binding affinity to catecholamines in obstructive sleep apnea.

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.

Cardiovascular Risk in Pediatric Renal Transplant Recipients.

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.

Renalase Potential as a Marker and Therapeutic Target in Chronic Kidney Disease.

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.

Renalase alleviates salt-induced kidney necroptosis and inflammation.

Recent evidence suggests that necroptosis may contribute to the development of kidney injury. Renalase is a novel secretory protein that exerts potent prosurvival and anti-inflammatory effects. We hypothesized that renalase could protect the kidney from salt-induced injury by modulating necroptosis. High salt and renalase treatments were administered to Dahl salt-sensitive (SS) rats, renalase knockout (KO) mice, and HK-2 cells. Furthermore, a cohort of 514 eligible participants was utilized to investigate the association between single nucleotide polymorphisms (SNPs) in the genes RIPK1, RIPK3, and MLKL, and the risk of subclinical renal damage (SRD) over 14 years. A high-salt diet significantly increased the expression of key components of necroptosis, namely RIPK1, RIPK3, and MLKL, as well as the release of inflammatory factors in SS rats. Treatment with recombinant renalase reduced both necroptosis and inflammation. In renalase KO mice, salt-induced kidney injury was more severe than in wild-type mice, but supplementation with renalase attenuated the kidney injury. In vitro experiments with HK-2 cells revealed high salt increased necroptosis and inflammation. Renalase exhibited a dose-dependent decrease in salt-induced necroptosis, and this cytoprotective effect was negated by the knockdown of PMCA4b, which is the receptor of renalase. Furthermore, the cohort study showed that SNP rs3736724 in RIPK1 and rs11640974 in MLKL were significantly associated with the risk of SRD over 14 years. Our analysis shows that necroptosis plays a significant role in the development of salt-induced kidney injury and that renalase confers its cytoprotective effects by inhibiting necroptosis and inflammation.

Renalase peptides reduce pancreatitis severity in mice.

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.

The effect of RNLS gene polymorphisms on preeclampsia susceptibility: a meta-analysis study.

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.

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Proteomic profiling of renal tissue of normo- and hypertensive rats with the renalase peptide RP220 as an affinity ligand.

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 ß-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.

Relation Between Exposure to Tobacco Smoke Assessed by Serum Cotinine Concentration and Questionnaire Method, and Serum Renalase Concentration-the Importance of the Coexistence of Arterial Hypertension and Other Cardiovascular Diseases.

Exposure to tobacco smoke (ETS) is one of the main risk factors for cardiovascular disease (CVD). Renalase is a protein that may play a role in the pathogenesis of CVD. The aim of the study was to assess the relationship between ETS and serum renalase concentration. A group of 109 patients was recruited for this study (49.7 ± 14.7 years). In accordance with the questionnaire, patients were divided into the following subgroups: subgroup A- declaring themselves active smokers (n = 36), subgroup B- declaring themselves non-smokers and exposed to environmental tobacco smoke (n = 35), subgroup C- declaring themselves non-smokers and not exposed to environmental tobacco smoke (n = 38). The same patients were divided based on cotinine concentration into the following subgroups: subgroup D- active smokers (n = 42), subgroup E- non-smokers exposed to environmental tobacco smoke (n = 66), and subgroup F- non-smokers not exposed to environmental tobacco smoke (n = 1). Serum cotinine concentration and serum renalase concentration were measured using ELISA tests. Serum renalase concentration was statistically significantly higher in subgroup C than in subgroups A and B and in subgroup E and F than in D. There was a negative correlation between serum cotinine concentration and serum renalase concentration (r = -0.41, p < 0.05). Regression analysis showed that higher BMI, higher diastolic blood pressure, coronary artery disease and higher serum cotinine concentration are independent risk factors of lower serum renalase concentration. The questionnaire method of assessing exposure to tobacco smoke was characterized by high sensitivity, but only moderate specificity, especially in terms of assessing environmental exposure to tobacco smoke. In summary, the study showed an independent relationship between exposure to tobacco smoke and lower serum renalase concentration.

Renalase Levels are Decreased in Maternal Blood and Placental Tissues in Pregnancies Associated with Preterm Preeclampsia.

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.

Investigation of the Relationship of Nesfatin-1, Adropin Levels and Claudin-2, Renalase Immunoreactivity with Kidney Function in an Experimental Hypertension Model.

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.

Selenoprotein P, peroxiredoxin-5, renalase, and total antioxidant status in patients with suspected obstructive sleep apnea.

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.

Coexistence of Cardiovascular Risk Factors and Blood Renalase Concentration.

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.

The search for potential hypotensive peptides in the amino acid sequence of human renalase and their identification in proteolytic fragments of this protein.

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.

Association Between Renalase Gene Polymorphism (rs2296545) and Hypertension in Egyptian Chronic Kidney Disease Patients.

Background Renalase gene polymorphisms are associated with an increased risk of essential hypertension, chronic kidney disease (CKD), heart disease, diabetes, and stroke. One of these polymorphisms is a common missense (rs2296545) polymorphism, which was reported to be related to hypertension. The aim of this work was to investigate the possible relation between renalase gene polymorphism (rs2296545) and hypertension in patients with CKD patients. Subjects and methods Ninety patients were included in this case-control study: 30 normotensive CKD patients, 30 hypertensive CKD patients, and 30 apparently healthy controls. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral whole blood, and renalase gene (rs2296545) polymorphism was genotyped in all patients and controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratios (OR) and their 95% CIs were calculated. Results We found that the CC genotype and the C allele renalase (rs2296545) were statistically associated with the risk of CKD (OR= 9.4; 95%CI 1.2-7.2; P= 0.036) and (OR= 3.78; 95%CI 1.57-9.08; P= 0.003), respectively. There was a statistically significant difference between the hypertensive CKD patients and the controls regarding the CC genotypes and the C allele, (26.7% versus 3.3%, P= 0.018) and (40% versus 11.7%, P< 0.001) for the CC genotype and the C allele, respectively. The mean values of systolic and diastolic blood pressure were higher in the normotensive CKD patients with the CC genotype compared to other genotypes (P= 0.014 and P= 0.022, respectively) and also were higher in hypertensive CKD patients with the CC genotype when compared to other genotypes (P= 0.001 for both). Conclusion This study demonstrated a statistically significant increase in the renalase gene (rs2296545) CC genotype and the C allele in CKD patients, especially hypertensive CKD.

The effect of renalase-derived peptides on viability of HepG2 and PC3 cells.

Renalase (RNLS) is a recently discovered 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. Certain evidence exists, that plasma/serum RNLS is not an intact protein secreted into the extracellular space, and exogenous recombinant RNLS is effectively degraded during short-term incubation with human plasma samples. Some synthetic analogues of the RNLS sequence (e.g. the Desir's peptide RP-220, a 20-mer peptide corresponding to the RNLS sequence 220-239) have effects on cell survival. This suggests that RNLS-derived peptides, formed during proteolytic processing, may have own biological activity. Based on results of a recent bioinformatics analysis of potential cleavage sites of RNLS (Fedchenko et al., Medical Hypotheses, 2022) we have investigated the effect of four RNLS-derived peptides as well as RP-220 and its fragment (RP-224) on the viability of two cancer cell lines: HepG2 (human hepatoma) and PC3 (prostate cancer). Two RNLS-derived peptides (RP-207 and RP-220) decreased the viability of HepG2 cells in a concentration dependent manner. The most pronounced and statistically significant effect (30-40% inhibition of cell growth) was observed at 50 µM concentration of each peptide. In the experiments with PC3 cells five of six RNLS-derived peptides had a significant impact on the cell viability. RP-220 and RP-224 decreased cell viability; however, no concentration dependence of this effect was observed in the range of concentrations studied (1-50 µM). Three other RNLS-derived peptides (RP-207, RP-233, and RP-265) increased viability of PC3 cells by 20-30%, but no concentration-dependence of this effect was found. Data obtained suggest that some RNLS-derived peptides may influence the viability of various cells and manifestation and direction of the effect (increase of decrease of the cell viability) is cell-type-specific.

The Multi-Faceted Nature of Renalase for Mitochondrial Dysfunction Improvement in Cardiac Disease.

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.

Selenoprotein P, Peroxiredoxin-5, Renalase and Selected Cardiovascular Consequences Tested in Ambulatory Blood Pressure Monitoring and Echocardiography.

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.

Cyclic-AMP response element binding protein (CREB) and microRNA miR-29b regulate renalase gene expression under catecholamine excess conditions.

AIMS: 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. MATERIALS AND METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.