Serum Corin Levels Research Articles

Circulating corin concentration is associated with risk of mortality and acute kidney injury in critically ill patients

Elevated serum corin concentrations in patients with cardiac diseases have been associated with adverse cardiovascular events and progressive renal dysfunction. This study aimed to determine the role of serum corin levels in predicting the incidence of acute kidney injury (AKI) and mortality in critically ill patients admitted to intensive care units (ICUs). We screened 323 patients admitted to the ICU in our institution from May 2018 through December 2019. After excluding patients receiving renal replacement therapy, 288 subjects were enrolled. Cases were divided equally into high (n = 144) and low (n = 144) corin groups according to median serum corin levels, using 910 pg/mL as the cut-off point. Patient characteristics and comorbidities were collected from medical records. The primary outcome was AKI within 48 h after ICU admission, while the secondary outcome was all-cause of mortality within 1 year. Compared with the low corin group, patients in the high corin group had higher prevalence rates of diabetes, cirrhosis, and nephrotoxic agent exposure; higher Sequential Organ Failure Assessment scores, white blood cell counts, proteinuria, and serum N-terminal pro-brain natriuretic peptide levels; but had lower initial estimated glomerular filtration rates. Furthermore, elevated serum corin was associated with higher risks of AKI within 48h of ICU admission (43.1% vs. 18.1%, p < 0.001) and all-cause mortality within one year (63.9% vs. 50.0%, p = 0.024). High corin level showed strongly positive results as an independent predictor of AKI (OR 2.15, 95% CI 1.11–4.19, p = 0.024) but not for the all-cause mortality after adjusting for confounding factors in multivariate analyses. Elevated circulating corin predicted AKI in critically ill patients, but did not predict all-cause mortality within 1 year. As a key enzyme in renin–angiotensin–aldosterone system, corin expression may be regulated through a feedback loop following natriuretic peptide resistance and desensitization of natriuretic peptide receptors in different critically ill status.

Chronic Kidney Disease Is Associated With Increased Cardiac Corin Expression But Decreased Proatrial Natriuretic Peptide Conversion Activity.

Background Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease. Corin converts proatrial natriuretic peptide into its active form after being activated by PCSK6 (proprotein convertase subtilisin/kexin type 6) protease. It remains unknown whether the PCSK6/corin/atrial natriuretic peptide pathway plays a role in CKD-induced cardiomyopathy. Methods and Results Serum corin, left ventricular mass index, and corin-left ventricular mass index correlation were compared between outpatients with versus without CKD. Cardiac corin expression and activity as well as serum corin were compared between 5/6 nephrectomy CKD animal models and sham controls. The effects of indoxyl sulfate, a uremic toxin, on cardiomyocytes were examined in vitro in H9c2 cells. A total of 543 patients were enrolled in this study. Serum corin levels were elevated in patients with CKD compared with levels in patients without CKD. Serum corin levels correlated negatively with left ventricular mass index in participants without CKD, but not in patients with CKD. Compared with sham controls, CKD mice had higher serum corin levels and increased cardiac expression of corin but reduced cardiac corin conversion activity. Indoxyl sulfate stimulated corin expression while suppressing serine protease activity in H9c2 cardiomyoblasts. Lower PCSK6 expression in CKD mouse hearts and indoxyl sulfate-treated H9c2 cardiomyoblasts may explain, at least partly, the observed CKD-associated reduction in corin activity. Conclusions In CKD, cardiac and serum levels of corin are increased, yet corin activity is suppressed. The latter may be attributable to reduced PCSK6 expression. These findings suggest that corin dysfunction may play a significant role in the pathogenesis of CKD-associated cardiomyopathy.

Low serum corin levels predict end-organ damage in patients with hypertensive crisis

The study aimed to investigate the predictive power of serum corin levels for distinguishing between hypertensive urgency (HU) and hypertensive emergency (HE) in patients with hypertensive crisis (HC) admitted to the emergency department. A total of 120 consecutive consenting adult patients diagnosed with HC and 55 age- and sex-matched healthy controls were enrolled. Blood pressure measurements [(systolic, diastolic, and mean arterial pressure (MAP)] and the evidence of end-organ damage at the first admission were recorded. Patients with HC were classified as patients with HE or HU according to the presence or absence of acute end-organ damage. Serum corin levels were compared between the 2 groups. The mean serum corin level was significantly lower in the HC group than in the control group; it was also lower in the HE group than in the HU group (p<0.001 for all). In the HE group, clinical features associated with end-organ damage included ST-elevation myocardial infarction (n=28, 46.7%), hemorrhagic stroke (n=11, 18.3%), ischemic stroke (n=11, 18.3%), and non-ST-elevation myocardial infarction (n=10, 16.7%). The receiving operator characteristic (ROC) analysis identified a serum corin cutoff value of 45 pg/mL for distinguishing patients with HE from patients with HU with 98.3% sensitivity and 95% specificity. Our findings suggest that serum corin levels play an important role in regulating blood pressure and are involved in the pathogenesis of HC. Low serum corin levels may predict end-organ damage and serve as a guide for diagnostic decision making in patients with HC.

Associations between potentially functional CORIN SNPs and serum corin levels in the Chinese Han population

BackgroundCorin is an important convertase involved in the natriuretic peptide system and may indirectly regulate blood pressure. Genetic factors relate to corin remain unclear. The purpose of the current study was to comprehensively examine the associations among CORIN SNPs, methylations, serum corin levels and hypertension.ResultsWe genotyped 9 tag-SNPs in the CORIN gene and measured serum corin levels in 731 new-onset hypertensive cases and 731 age- and sex-matched controls. DNA methylations were tested in 43 individuals. Mendelian randomization was used to investigate the causal associations. Under additive models, we observed associations of rs2289433 (p.Cys13Tyr), rs6823184, rs10517195, rs2271037 and rs12509275 with serum corin levels after adjustment for covariates (P = 0.0399, 0.0238, 0.0016, 0.0148 and 0.0038, respectively). The tag-SNP rs6823184 and SNPs that are in strong linkage disequilibrium with it, i.e., rs10049713, rs6823698 and rs1866689, were associated with CORIN gene expression (P = 2.38 × 10− 24, 5.94 × 10− 27, 6.31 × 10− 27 and 6.30 × 10− 27, respectively). Neither SNPs nor corin levels was found to be associated with hypertension. SNP rs6823184, which is located in a DNase hypersensitivity cluster, a CpG island and transcription factor binding sites, was significantly associated with cg02955940 methylation levels (P = 1.54 × 10− 7). A putative causal association between cg02955940 methylation and corin levels was detected (P = 0.0011).ConclusionThis study identified potentially functional CORIN SNPs that were associated with serum corin level in the Chinese Han population. The effect of CORIN SNPs on corin level may be mediated by DNA methylation.

The role of G protein-associated estrogen receptor (GPER) 1, corin, raftlin, and estrogen in etiopathogenesis of intrauterine growth retardation

Objective: The aim of the present study was to detect the role of G protein-associated estrogen receptor (GPER) 1, corin, raftlin and estrogen in etiopathogenesis of intrauterine growth retardation (IUGR).Materials and methods: The present study was designed prospectively between January 2017 and May 2018. The study group included 32 patients with unexplained IUGR and 32 healthy pregnant women who gave birth at term among the patients who referred to obstetrics clinic of a tertiary reference hospital. Intrauterine growth retardation (IUGR) was accepted as birth weight below 10th percentile according to the estimated fetal weight. Exclusion criteria were as follows: the patients with renal or hepatic dysfunction, presence of any chronic disease, smoker patients, preeclampsia, acute or chronic inflammatory diseases, body mass index as <18 kg/m2 and >25 kg/m2, structural or chromosomal abnormality in fetus Estradiol (E2), estriol (E3), GPER, corin, and raftlin levels were analyzed in maternal serum and placental tissue homogenate through ELISA method.Results: Serum levels of GPER-1, raftlin, and E3 were significantly lower in IUGR group when compared with the control group (p < .05 for all). Serum corin and E2 levels were similar between two groups. GPER-1, E2, E3, raftlin, and corin levels in placental homogenate were found significantly higher in the control group (p < .05 for all).Conclusion: Although maternal, fetal, and placental causes take place in etiopathogenesis of IUGR, exact etiological factor is not revealed in majority of the IUGR cases. The present study serves as the first study revealing the role of the decrease in GPER-1 and raftlin in maternal serum and placental levels on the etiopathogenesis of IUGR. Furthermore, the decrease in placental corin expression of the cases with IUGR was detected first in the literature. The present study reveals a potential therapeutic use of GPER-1, corin, and raftlin for IUGR.

Serum Corin Level Is Associated With Subsequent Decline in Renal Function in Patients With Suspected Coronary Artery Disease.

BackgroundHigher circulatory corin in patients with cardiac diseases is associated with improved cardiovascular outcomes, and chronic cardiac dysfunction is a well‐known cause of progressive renal dysfunction. This study aimed to determine the role of serum corin in predicting short‐term and long‐term renal outcomes after contrast exposure in patients with suspected coronary artery disease.Methods and ResultsFour hundred one patients who had received coronary angiography were enrolled. Serum corin levels were determined before administration of contrast media. Contrast‐induced nephropathy was defined as a rise in serum creatinine of 0.5 mg/dL or a 25% increase from baseline within 48 hours after the procedure. Progressive renal dysfunction was defined as >50% decrease in estimated glomerular filtration rate after discharge. All patients were followed up for at least 1 year or until the occurrence of death after coronary angiography. Overall, contrast‐induced nephropathy occurred in 23 (5.7%) patients. During a median follow‐up of 529 days, 44 (11.0%) cases had subsequent decline in renal function. After adjustment for demographic characteristics, kidney function, traditional risk factors, and medications, lower corin level was found to be independently associated with higher risk for progressive renal dysfunction (hazard ratio, 0.23; 95% confidence interval, 0.12–0.44) but not for contrast‐induced nephropathy. This inverse correlation remained evident in patients with underlying chronic kidney disease, coronary artery disease, or heart failure.ConclusionsLower baseline serum corin was associated with higher risk of renal function decline in patients undergoing coronary angiography. Further studies are needed to verify these results.

Serum corin is associated with the risk of chronic heart failure.

It has been well documented that corin is a critical protease involved in the regulation of blood pressure and cardiac function. We performed a case-control study to determine whether serum corin is associated with the risk of chronic heart failure (CHF). We included 484 consecutive CHF patients and 484 control subjects to investigate the potential relationship between serum corin and CHF using logistic regression analysis. Compared with healthy controls, the CHF patients were more likely to have histories of hypertension and diabetes, and had higher levels of N-terminal pro-brain natriuretic peptide and lower levels of corin. The odds ratios of ischemic and non-ischemic HF were significantly reduced with the growing levels of serum corin after multivariate adjustment. Moreover, the decrease in serum corin levels seemed to be associated with the severity of CHF. In conclusion, our study suggested that serum corin levels were reduced in CHF patients and inversely correlated with the incidence of ischemic and non-ischemic HF.

Increased levels of soluble corin in pre-eclampsia and fetal growth restriction

Atrial natriuretic peptide is biologically activated by the atrial natriuretic peptide-converting enzyme, corin, and has an important role in regulating blood pressure. We detected elevated serum corin levels in women with pre-eclampsia. Interestingly, the serum corin levels were also found to be elevated in pregnancies with a related disorder, unexplained fetal growth restriction (FGR) without hypertension, suggesting that this phenomenon is not simply a response to maternal hypertension. CORIN mRNA levels were not elevated in placentas from pre-eclampsia or unexplained FGR cases. Likewise, similar signal intensities were found for corin in placental syncytiotrophoblast cells by immunostaining. In contrast, corin signals were higher in maternal decidua cells from pre-eclampsia and unexplained FGR cases. These data suggest that corin may be upregulated in maternal decidua in response to an etiologic pathway that is common to pre-eclampsia and FGR.

Association between serum corin levels and risk of acute myocardial infarction

BackgroundAccumulating evidence has indicated that corin plays critical roles in regulating salt-water balance, blood pressure and cardiac function by activating natriuretic peptides. The present case–control study was designed to evaluate the association of serum soluble corin with acute myocardial infarction (AMI). MethodsWe enrolled 856 consecutive AMI patients and 856 control subjects and explored the possible relation between serum corin levels and AMI risk using logistic regression model. ResultsPatients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the controls. Serum levels of corin were remarkably reduced in AMI patients (825±263pg/ml) compared with those in healthy controls (1246±425pg/ml). Odds ratios of ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) were significantly decreased with the increasing levels of serum corin in both men and women (P for trend, <0.001) after adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. ConclusionsOur study demonstrates that serum levels of corin are significantly decreased in AMI patients, and it is inversely associated with the incidences of STEMI and NSTEMI in both men and women.

Association between serum soluble corin and obesity in Chinese adults: a cross-sectional study.

Corin has been suggested to be associated with obesity by cell- and animal-based studies. However, the association has not yet been studied in populations. Here, the aim was to explore the association in a general population of China. This was a cross-sectional study. Data on demographic information, lifestyle risk factors, and personal medical history were collected; body mass index, waist circumference, and blood pressures were measured; and serum corin, blood lipids, and blood glucose were determined in 2498 participants aged above 30 years. Log-transformed corin correlated to body mass index (r = 0.197, P < 0.001) and waist circumference (r = 0.289, P < 0.001). In the risk factor-adjusted analysis, compared with participants in the lowest quartile of serum corin, participants in the 4th quartile had significantly increased risk of prevalent overweight or obesity (OR = 2.26, 95% CI: 1.67-3.04) and central obesity (OR = 1.74, 95% CI: 1.30-2.34). ORs of overweight or obesity and central obesity positively and significantly increased with serum corin levels (P for trend < 0.001). Serum soluble corin was significantly and positively associated with obesity. Our findings suggested that serum soluble corin may be a marker or risk factor for obesity.

Association Between High Serum Soluble Corin and Hypertension: A Cross-Sectional Study in a General Population of China.

Corin has been suggested to be associated with hypertension by cell- and animal-based studies. However, the association still lacks population-based evidence which critically promotes translation from basic research to clinical and preventive practice. Here, we aimed to explore the association in a general population of China. From January to May 2010, we conducted a cross-sectional study in 2,498 participants aged above 30 years, residing in Gusu district of Suzhou. Serum soluble corin and blood pressure were measured. Hypertensive participants had a higher level of serum corin than nonhypertensive participants (median (interquartile range): 1,836.83 (1,497.85-2,327.87) pg/ml vs. 1,579.14 (1,322.18-1,956.82) pg/ml, P < 0.001). Higher serum corin was positively associated with prevalent hypertension (odds ratio (OR) = 2.01, P < 0.001). In the multiple analysis, participants in the third (OR = 1.43, P = 0.007) and fourth (OR = 1.96, P < 0.001) quartiles had significantly increased odds of hypertension compared to those in the lowest quartile of serum corin. ORs of hypertension positively and significantly increased with serum corin levels (P for trend <0.001). Further subgroup analysis showed that ORs of hypertension associated with high corin (over the median level of serum corin: 1,689.20 pg/ml) were still significant in subgroups by age, body mass index, total cholesterol, low-density lipoprotein cholesterol, and fasting plasma glucose (all P < 0.05). Our study showed that hypertensive participants had an increased serum corin level compared to those without hypertension. This finding suggests that corin may play a role in the pathology of hypertension.

Reduced serum corin levels in patients with osteoporosis

BackgroundCorin is a cardiac protease that activates the natriuretic peptides. Corin is also expressed in chondrocytes and bone marrow-derived mesenchymal stem cells that undergo osteogenic differentiation, suggesting a potential role of corin in bone formation and homeostasis. MethodsTo test if corin levels are altered in patients with bone disease, we used ELISA to measure corin and osteocalcin levels in serum samples from healthy controls (n=134) and patients with osteopenia (n=53) and osteoporosis (n=101). ResultsIn patients with osteopenia and osteoporosis, serum corin levels were 510±228 and 478±183pg/ml, respectively, which were significantly lower than that in healthy controls (682±240pg/ml) (both p values<0.001). The reduced serum corin levels were found in both male and female patients. In multiple linear regression analysis, bone mineral density was identified as an independent predictor for serum corin levels. In patients with osteopenia and osteoporosis, but not normal controls, a negative correlation was found between serum corin and osteocalcin levels. ConclusionSerum corin levels were reduced in patients with osteoporosis and the reduction was associated with high rates of bone turnover. Low serum corin levels may reflect impaired bone homeostasis in patients with osteoporosis.

Serum corin is reduced and predicts adverse outcome in non-ST-elevation acute coronary syndrome

The aim of the current study was to describe the role of corin, an enzyme that cleaves pro-atrial natriuretic peptide and pro-brain natriuretic peptide into their active peptides, in patients with acute coronary syndrome (ACS). Serum corin level was studied in patients with non-ST-elevation ACS who underwent percutaneous coronary intervention (n=152) and in control volunteers (n=103). The corin level was lower in acute coronary syndrome patients (798±288 pg/ml) than in the controls (1165±613 pg/ml, p<0.0001). Those acute coronary syndrome patients who developed major adverse cardiovascular events (MACE; 60.9%) within 3 years of discharge had lower corin levels than the patients who did not experience major adverse cardiovascular events (698.16±233.67 vs. 952.1±297.81 pg/ml, p<0.0001). Using a multiple logistic regression model, corin level was a significant predictor of post-ACS MACE: p=0.0004 for 50 pg/ml steps, AUC 0.791, while p<0.0001, and AUC 0.804 using corin and brain natriuretic peptide as predictors. Patients with non-ST-elevation ACS have lower serum corin levels than controls. Corin levels are lower in ACS patients who later experience MACE and thus might be predictor for MACE. This new putative biomarker may be useful, either alone or in combination with other biomarkers, for cardiovascular risk stratification assessment and outcome prediction in ACS patients.

Enzyme-linked immunoabsorbent assay for detection of human serine protease corin in blood

Background Corin is a tissue type II transmembrane protein that converts pro-atrial natriuretic peptides and pro-brain natriuretic peptide to their active forms. Despite their protecting effect, high levels of these peptides indicate a bad prognosis. One of the possible explanations to this paradox is reduced cleavage due to low corin levels. The purpose of this study was to develop an assay to detect blood levels of corin. Methods ELISA was developed using rat monoclonal antibody to recombinant human corin as capture antibody, and biotinylated goat anti-human corin as detection antibody. Results Based on known corin concentration as standards, the ideal capture antibody concentration was 500 ng/ml, and 200 ng/ml for detection antibody. The coefficient of variation was 5.7% for inter-assay and 3.9% for intra-assay precision. Corin levels were stable when stored at room temperature for 1 day, for 3 days at 4 °C or up to 1 year in − 35 °C. Human serum corin levels were reproducibly measured in individuals and found to range from 296 to 2590 pg/ml. Conclusions The immunoabsorbent assay developed in this study can accurately and reliably determine human serum corin levels, and is suitable for simple screening of corin in clinical practice.