Serum Prorenin Research Articles

Plasma and serum prorenin concentrations in diabetes, hypertension, and renal disease.

Although the renin-angiotensin-aldosterone system plays a crucial role in fluid homeostasis and cardiovascular disease pathophysiology, measurements of plasma prorenin levels are still unavailable in clinical practice. We previously found that prorenin molecules in human blood underwent significant posttranslational modifications and were undetectable using immunological assays that utilized antibodies specifically recognizing unmodified recombinant prorenin. Using a sandwich enzyme-linked immunosorbent assay that captures posttranslationally modified prorenins with their prosegment antibodies, we measured plasma and serum prorenin concentrations in 219 patients with diabetes mellitus, hypertension and/or renal disease and compared them with those of 40 healthy controls. The measured values were not significantly different from those of the healthy controls and were 1,000- to 100,000-fold higher than previously reported levels determined using conventional assay kits. Multiple regression analyses showed that body weight, serum albumin levels, and serum creatinine levels negatively correlated with plasma prorenin levels, while the use of loop diuretics was associated with elevated plasma prorenin levels. Blood pressure, HbA1c, and plasma renin activity were not independent variables affecting plasma prorenin levels. In contrast, serum prorenin levels were unaffected by any of the above clinical parameters. The association of the plasma prorenin concentration with indices reflecting body fluid status suggests the need to scrutinize its role as a biomarker, while serum prorenins are less likely to have immediate diagnostic value.

Independent serum markers of corpora lutea function after gonadotropin-releasing hormone agonist trigger and adjuvant low dose human chorionic gonadotropin in in vitro fertilization

To characterize corpora lutea (CL) function after gonadotropin-releasing hormone agonist (GnRHa) trigger with the use of adjuvant human chorionic gonadotropin (hCG). Secondary analysis of serum from prospective randomized clinical trial. University-based fertility center. Women under 40years of age at risk of ovarian hyperstimulation syndrome (OHSS) with serum E2 level <4,000 pg/mL. All subjects underwent ovarian stimulation with the use of a GnRH antagonist protocol. Within a larger study, subjects were randomized to receive 1,000 IU hCG at the time of GnRHa trigger and placebo at the time of vaginal oocyte retrieval (VOR) or placebo at the time of GnRHa trigger and 1,500 IU hCG at the time of VOR. Luteal phase and early pregnancy curves of serum prorenin and 17α-hydroxyprogesterone (17OH-P). Thirty subjects enrolled in this secondary analysis. Serum 17OH-P peaked in the early luteal phase, 5days after GnRHa trigger, with a nadir in the mid-luteal phase 9days after trigger. Serum prorenin peaked in the luteal phase 2days after GnRHa trigger, independently from adjuvant hCG timing, and reached a nadir at 9days after trigger. CL function appears higher when adjuvant hCG is given at VOR compared with adjuvant hCG given at the time of trigger. CL function, as interpreted by proxy measures of serum prorenin and 17OH-P with pregnancy, continues despite GnRHa trigger. Both options for adjuvant hCG timing are sufficient for CL rescue and successful pregnancy, so the potential for OHSS risk with increased CL activity after hCG at VOR should be considered. NCT01815138.

Prorenin and secreted frizzled-related protein 4 levels in women with gestational diabetes mellitus.

This study was designed to investigate prorenin and secreted frizzled-related protein 4 (SFRP4) levels in pregnancies with or without gestational diabetes mellitus (GDM). A total of 76 pregnant women were included in the study. Thirty-five of the pregnant women were included in GDM group according to the results of oral glucose tolerance tests (OGTT) and 41 of them were included in the control group. In the group with GDM, SFRP4 value was found to be significantly higher than that of the control group (5.59 ± 3.32 ng/mL vs 4.05 ± 2.15 ng/mL; p = 0.017). Women with GDM had significantly higher serum prorenin levels compared with control group [737 (427-1339) pg/mL vs. 535 (376-725) pg/mL; p = 0.009]. There was a significant positive association between prorenin and SFRP4 levels in GDM (r = 0.91; p < 0.001) and control groups (r = 0.42; p = 0.002) and whole pregnancies (r = 0.75; p = 0.002). We have shown that prorenin and SFRP4 were significantly elevated in GDM patients when compared to healthy control group. Furthermore, we found that there was a positive correlation between prorenin and SFRP4 (Tab. 1, Fig. 2, Ref. 38).

Serum prorenin levels are not associated with ocular diseases in non-diabetic subjects.

To determine if the serum prorenin level is useful for detecting ocular disease in a non-diabetic population. We enrolled non-diabetic men (n = 402) and women (n = 349) in our study. We used the antibody-activating direct enzyme kinetic assay of human prorenin to determine serum prorenin levels. We performed multiple regression analysis to determine the factors that affect serum prorenin levels, such as: age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, fasting blood sugar, and HbA1c or estimated glomerular filtration rate. Our study subjects were divided into groups by their ophthalmologic diagnosis. One-way analysis of variance (ANOVA) was performed to detect a significant difference in the serum prorenin levels among the groups. There were no significant differences in serum prorenin levels among the ocular diseases and disorders. The DBP was negatively correlated with serum prorenin levels in men (r = - 0.1992; p = 0.021) and in women (r = - 0.2067; p = 0.031). Considering the current results and those of previous studies together, we found that the prorenin value is useful solely for predicting development of diabetic retinopathy in adults.

Estimation of pro-renin as a prognostic marker for renal function in PUV patients

ObjectiveTo estimate serum pro-renin, and its clinical significance, as a marker of chronic renal disease in posterior urethral valve (PUV) patients. Patients and methodsForty patients with a PUV that were admitted to the hospital between 2010 and 2012 were reviewed. Twenty age-matched patients who were admitted for other non-urological diseases were selected for control. Clinical parameters, serum creatinine, urea, eGFR (estimated glomerular filtration rate) and serum pro-renin were analysed before and after valve ablation. ResultsForty patients with PUV were included in the study. Three groups were formed according to age: <1 year, 1–3 years, >3 years. Pro-renin was measured using an ELISA (enzyme linked immunosorbent assay) kit and ‘Graph Pad Prism’ Software. The Spearman's rho test was used for correlation. Serum pro-renin had a negative correlation with the age group (correlation coefficient −0.395, P-value 0.012), eGFR (correlation coefficient −0.850, P-value < 0.001) and follow-up eGFR (correlation coefficient −0.471, P-value 0.002). The pro-renin level correlated positively with serum creatinine at presentation (correlation coefficient 0.671, P-value < 0.001), blood urea at initial presentation (correlation coefficient 0.684, P-value < 0.001), serum creatinine at follow-up (correlation coefficient 0.546, P-value < 0.001) and blood urea at follow-up (correlation 0.603, P-value < 0.001). ConclusionPro-renin measured before PUV repair is associated with renal function three months after surgery.

Roles of the (pro)renin receptor in the kidney.

Prorenin receptor (PRR) is a multi-functioning protein possessing at least four different roles: (1) working as a receptor for renin and prorenin producing angiotensin I from angiotensinogen thus enhancing the tissue renin-angiotensin system; (2) inducing intracellular signals when a ligand binds to PRR; (3) participating in the functions of vacuolar proton ATPase; and (4) constituting the Wnt signaling receptor complex. Here, the roles of PRR in kidney physiology and diabetic conditions as well as recent findings regarding a soluble form of PRR are discussed. We also propose the possible mechanism concerning diabetic nephropathy as "trade-off hypothesis" from a PRR point of view. In brief, under hyperglycemic conditions, injured podocytes degrade degenerated proteins and intracellular organelles which require V-ATPase and PRR for vesicle internal acidification. Sustained hyperglycemia overproduces PRR molecules, which are transported to the transmembrane and bind to increased serum prorenin in the diabetic condition. This enhances tissue renin-angiotensin system and PRR-mediated mitogen-activated protein kinase signals, resulting in increased injurious molecules such as transforming growth factor-β, cyclooxygenase2, interleukin-1β, and tumor necrosis factor-α ending in diabetic nephropathy progression. Although many findings led us to better PRR understanding, future works should elucidate which PRR functions, of the four discussed here, are dominant in each cell and kidney disease context.

Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease

Prorenin, the precursor of renin, binds to the (pro)renin receptor [(P)RR] and triggers intracellular signaling. The ligand binding sites of (P)RR are disconnected and are present in the soluble form of the receptor in serum. Given that the clinical significance of serum prorenin and soluble (P)RR in chronic kidney disease (CKD) is unclear, we investigated the relationship between serum prorenin, soluble (P)RR, and various clinical parameters in patients with CKD. A total of 374 patients with CKD were enrolled. Serum samples were collected, and the levels of soluble (P)RR and prorenin were measured using ELISA kits. Serum creatinine (Cr), blood urea nitrogen (BUN), uric acid (UA), hemoglobin (Hb), soluble secreted α-Klotho, and the urine protein/Cr ratio were also measured. Similarly, clinical parameters were also evaluated using serum and urine sample collected after 1year (n=204). Soluble (P)RR levels were positively associated with serum Cr (P<0.0001, r=0.263), BUN (P<0.0001, r=0.267), UA (P<0.005, r=0.168) levels, CKD stage (P<0.0001, r=0.311) and urine protein/Cr ratio (P<0.01, r=0.157), and inversely with estimated glomerular infiltration rate (eGFR) (P<0.0001, r=-0.275) and Hb (P<0.005, r=-0.156). Soluble (P)RR levels were inversely associated with α-Klotho levels (P<0.001, r=-0.174) but did not correlate with prorenin levels. With respect to antihypertensive drugs, soluble (P)RR levels were significantly lower in patients treated with an angiotensin II receptor blocker (ARB) than in those without ARB therapy (P<0.005). Soluble (P)RR levels were significantly lower in CKD patients with diabetes mellitus or primary hypertension than in those without these conditions (P<0.05). In contrast, serum levels of prorenin did not correlate with parameters related to renal function. Serum prorenin levels were significantly higher in CKD patients with diabetes mellitus than in nondiabetic patients (P<0.05), but not in CKD patients with hypertension (P=0.09). Finally, with respect to the relationship between basal soluble (P)RR levels and the progression rates of renal function, soluble (P)RR levels were positively associated with ΔCr (P<0.05, r=0.159) and inversely associated with ΔeGFR (P<0.05, r=-0.148). Serum levels of soluble (P)RR correlated with the stage of CKD. Our findings suggest that soluble (P)RR may be involved in renal injury and influence the progression of CKD.

The Progression of Serum Prorenin Concentration during Pregnancy

Objective: An association between the renin-angiotensin system and the pathogenesis of pregnancy-induced hypertension has been reported. The prorenin receptor was discovered in 2002, and Wanatabe et al. reported that women with plasma soluble prorenin receptor concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia. We evaluated serum prorenin concentrations during pregnancy, and we assessed the incidence of pregnancy-induced hypertension. Methods: We measured serum prorenin concentrations in 430 pregnant women (565 samples). Regression analysis was performed to determine the associations between the serum prorenin level and maternal/neonatal complications. Results: The serum prorenin concentration and gestational age had a positive correlation in non-pregnancyinduced hypertension in women with singleton pregnancies (Spearman rank-correlation coefficient, -0.215: p<0.0001). The serum prorenin concentration in women with multiple pregnancies was significantly higher than that in women with singleton pregnancies (multiple linear regression analysis, p<0.0001). Low prorenin levels in the third trimester (≤20.1 percentile) were significantly associated with pregnancy-induced hypertension (adjusted odds ratio, 18.16: 95% confidential interval, 1.95-412.41: p=0.0107). Conclusion: The serum prorenin levels during pregnancy may be adversely correlated with the prorenin receptor, and low prorenin levels during late pregnancy were significantly associated with pregnancy-induced hypertension.

Higher levels of prorenin predict development of diabetic retinopathy in patients with type 2 diabetes

The aim was to determine whether serum prorenin levels affect the development of diabetic retinopathy (DR) in type 2 diabetes. Baseline serum prorenin levels were measured in 196 patients (85 males, 111 females) with type 2 diabetes without DR using the antibody-activating direct prorenin assay. The fundi were checked regularly. The participants were divided into two groups based on the serum prorenin levels (high and low). We used Kaplan-Meyer analysis to detect differences in the development of DR between the two groups within the same gender. Kaplan-Meyer analysis showed that males with a high serum prorenin level tended to develop DR earlier and more frequently than males with a low prorenin level ( p = 0.004 by the log rank test). However, there was no difference in the development of DR between high and low groups in females (p = 0.58). Serum prorenin levels in males with type 2 diabetes could be a new prognostic indicator of the development of DR.

Prorenin Levels in Retinopathy of Prematurity

To evaluate serum prorenin levels in preterm infants with or without retinopathy of prematurity (ROP). Noncomparative retrospective case control study. Serum prorenin levels in children with a gestational age younger than 36 weeks were measured with antibody-activating direct enzyme kinetic assay. The mean prorenin concentrations were higher in preterm infants with ROP than in infants without ROP at every time point: from 26 to 30 weeks, 2326 +/- 334 microg/ml (mean +/- SE [standard error]) (n = 3) and 1164 +/- 234 microg/ml (n = 3), respectively (P < .05); from 31 to 35 weeks, 1760 +/- 496 microg/ml (n = 10) and 957.1 +/- 139 microg/ml (n = 25) (P < .05); from 36 to 40 weeks, 958.2 +/- 194.2 microg/ml (n = 23) and 470.1 +/- 32.6 microg/ml (n = 67) (P < .01); and from 41 to 45 weeks, 575.8 +/- 148.4 (n = 9) and 385.6 +/- 47.9 (n = 13), which is not significantly different. Prorenin levels in preterm infants can predict which infants will develop ROP.

Sex difference and possible relationship to microvascular complications of serum prorenin levels in type 2 diabetic patients, measured by a novel antibody-activating direct enzyme kinetic assay

Prorenin, a precursor of renin, was measured in sera from normal subjects and type 2 diabetic patients, using a newly developed antibody-activating direct enzyme kinetic assay. Levels of prorenin were examined in relationship to diabetic microangiopathies. The levels of antibody-activating direct prorenin (AAD-PR) were approximately 1.5-fold higher than levels of prorenin measured by a conventional enzyme-activating method. AAD-PR levels were significantly higher in males than in females and in diabetic patients than in normal subjects. Moreover, AAD-PR levels were higher in diabetic patients with microalbuminuria and even higher in those with macroalbuminuria. In normoalbuminuric diabetic patients, AAD-PR levels were higher in those with retinopathy. Furthermore, a significant positive correlation was seen between the AAD-PR levels and HbA lc in normoalbuminuric diabetic subjects without retinopathy. Thus, the determination of circulating serum prorenin measured as AAD-PR is related to glycemia and in type 2 diabetic patients may be a risk marker of diabetic microangiopathy. More studies are necessary to determine whether AAD-PR may actually predict the development of microangiopathy.

Serum prorenin levels determined by newly developed direct method in diabetic patients

Serum prorenin levels determined by newly developed direct method in diabetic patients

Reduction of psychotic symptoms in patients with lewy body-like symptoms treated with olanzapine

Serum total renin is increased before microalbuminuria in diabetes. Serum prorenin is increased in patients with insulin-dependent diabetes mellitus (IDDM) with microvascular complications. The present longitudinal study investigated whether increases in serum total renin concentration (TRC, active+prorenin) can predict the development of microalbuminuria in IDDM patients over a 10 year period. TRC and albumin excretion rates (AER) were determined in 78 IDDM patients who were followed longitudinally for 10.4 ± 0.2 (mean ± SE) years. Twelve patients had progressively increasing albuminuria (progressors), and these were compared to 66 patients in whom albuminuria did not rise (non-progressors). The two groups had similar duration of diabetes, age, follow-up, glycemic control and blood pressure at the start of the study. Serum TRC was increased in progressors [350 (1.1) mIU/liter, geometric mean (tolerance factor)] compared to non-progressors [189 (1.2)] after 5 to 10 years duration of diabetes, and continued to rise in this group, reaching a mean of 923 mIU/liter (normal range 131 to 170) after 20 years of diabetes. When serial measurements of TRC and AER were compared in individual progressors, a significant increase in TRC was apparent up to five years before the onset of microalbuminuria. Microalbuminuria in patients with IDDM is preceded by a substantial increase in serum TRC, suggesting that serum TRC may predict the subsequent development of incipient nephropathy.

Increase in serum prorenin precedes onset of microalbuminuria in patients with insulin-dependent diabetes mellitus.

The renin-angiotensin system is possibly involved in the pathogenesis of diabetic nephropathy. The most striking change in renin-angiotensin system components in blood of patients with diabetic nephropathy is an increased prorenin concentration. We investigated prospectively serum concentrations of renin-angiotensin system components and the time course of prorenin increase in normoalbuminuric diabetic patients developing microalbuminuria. Patients (n = 199) with Type I (insulin-dependent) diabetes mellitus and normoalbuminuria at baseline were prospectively followed for 10 years. The prorenin concentrations and other variables possibly associated with the occurrence of microalbuminuria, were investigated by Cox-regression analysis. Of the patients 29 developed microalbuminuria. Glycated haemoglobin values were higher at baseline in these patients. Serum prorenin was similar at baseline but rose in the 29 patients before the development of microalbuminuria and was stable in patients with stable albumin excretion. Renin, angiotensinogen and angiotensin converting enzyme serum concentrations were stable in both groups. Prorenin and glycated haemoglobin were independent prognostic factors for the development of microalbuminuria. A prognostic index, based on these variables, was constructed to estimate the relative risk of developing microalbuminuria. Increase in serum prorenin precedes onset of microalbuminuria in normotensive patients with insulin-dependent diabetes mellitus. High concentrations of prorenin in combination with high values of glycated haemoglobin can be used as a predictor of development of microalbuminuria.

Serum total renin is increased before microalbuminuria in diabetes

Serum prorenin is increased in patients with insulin dependent diabetes mellitus (IDDM) with microvascular complications. The present longitudinal study investigated whether increases in serum total renin concentration (TRC, active+prorenin) can predict the development of microalbuminuria in IDDM patients over a 10 year period. TRC and albumin excretion rates (AER) were determined in 78 IDDM patients who were followed longitudinally for 10.4 +/- 0.2 (mean +/- SE) years. Twelve patients had progressively increasing albuminuria (progressors), and these were compared to 66 patients in whom albuminuria did not rise (non-progressors). The two groups had similar duration of diabetes, age, follow-up, glycemic control and blood pressure at the start of the study. Serum TRC was increased in progressors [350 (1.1) mIU/liter, geometric mean (tolerance factor)] compared to non-progressors [189 (1.2)] after 5 to 10 years duration of diabetes, and continued to rise in this group, reaching a mean of 923 mIU/liter (normal range 131 to 170) after 20 years of diabetes. When serial measurements of TRC and AER were compared in individual progressors, a significant increase in TRC was apparent up to five years before the onset of microalbuminuria. Microalbuminuria in patients with IDDM is preceded by a substantial increase in serum TRC, suggesting that serum TRC may predict the subsequent development of incipient nephropathy.

Prorenin and renal function in NIDDM patients with normo‐ and microalbuminuria

To assess whether prorenin is elevated and perhaps a predictor of deteriorations in albuminuria and/or renal function in NIDDM patients with normo- and microalbuminuria. A cross-sectional and a longitudinal study. Outpatient diabetic clinic. Twenty-eight NIDDM patients (16 with normoalbuminuria, 12 with microalbuminuric) and 16 healthy subjects, matched for sex, age and BMI. Fifteen patients were reinvestigated after (mean [range]) 3.1 (2.1-4.3) years. Serum prorenin and renin, urinary albumin excretion rate, and glomerular filtration rate. Serum prorenin was similar in both normoalbuminuric (116x/divided by) 1.9 microU ml-1 (geometric meanx/divided by antilog SD) and microalbuminuric (124x/divided by) 1.7 microU ml-1) as well as in healthy control subjects (90x/divided by) 1.7 microU ml-1). Prorenin did not correlate to either urinary albumin excretion rate or glomerular filtration rate. No difference between baseline and follow-up levels of albuminuria, glomerular filtration rate or prorenin were observed. The annual changes in albuminuria, glomerular filtration rate and prorenin were not correlated, and no correlation was found between baseline prorenin levels and annual changes in albuminuria or glomerular filtration rate. Serum prorenin levels are not elevated in either normoalbuminuric or microalbuminuric NIDDM patients, and serum prorenin is not a valid predictor of long-term changes in albuminuria in this patient group.

High serum prorenin is a risk factor for micro-albuminuria in patients with insulin-dependent diabetes mellitus. A 10-year follow-up study

High serum prorenin is a risk factor for micro-albuminuria in patients with insulin-dependent diabetes mellitus. A 10-year follow-up study