Plasma Prorenin Concentrations 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.

Circulating prorenin: its molecular forms and plasma concentrations.

The renin-angiotensin-aldosterone system plays pivotal roles in the maintenance of fluid homeostasis and in the pathophysiology of major human diseases. However, the molecular forms of plasma renin/prorenin have not been fully elucidated, and measurements of plasma prorenin levels are still unavailable for clinical practice. We attempted to evaluate the molecular forms of human plasma prorenin and to directly measure its concentration without converting it to renin to determine its activity. Polyacrylamide gel electrophoresis and subsequent immunoblotting using antibodies that specifically recognise prosegment sequences were used to analyse its molecular forms in plasma. We also created a sandwich enzyme-linked immunosorbent assay suitable for directly quantifying the plasma concentration. The plasma level in healthy people was 3.0-13.4 μg/mL, which is from 3 to 4 orders of magnitude higher than the levels reported thus far. Plasma immunoreactive prorenin consists of three major distinct components: a posttranslationally modified full-length protein, an albumin-bound form and a smaller protein truncated at the common C-terminal renin/prorenin portion. In contrast to plasma renin activity, plasma prorenin concentrations were not affected by the postural changes of the donor. Hence, plasma prorenin molecules may be posttranslationally modified/processed or bound to albumin and are present in far higher concentrations than previously thought.

Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor β (TGFβ) 1 (TGFβ1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, β-catenin, and Akt-mediated signals.

Abstract P472: Prorenin Independently Causes Hypertension And Renal and Cardiac Fibrosis In Cyp1a1-Prorenin Transgenic Rats

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In this study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (Cyp1a1 prorenin transgenic male and female rats and nontransgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration rose from 23±6 to 208±44 (μg/ml) and MAP increased from 77±5 to 138±17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of TGFß1, PAI-1, collagen and fibronectin. These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight. Cardiac collagen in interstitial and perivascular area was prominent, accompanied by the increases in mRNA contents of ANP, BNP, ß-MHC, TGFß1 and PAI-1 in the heart tissue. Furthermore, renal protein levels of phosphor-NF-kB-p65 and MCP-1, NAPDH oxidase and MDA, phospho-ß-catenin and phospho-Akt were dramatically increased in prorenin overexpressed rats. These results indicate that prorenin, without being converted to renin, causes arterial hypertension, renal and cardiac fibrosis independently via the induction of inflammation, oxidative stress and the ß-catenin and Akt-mediated signals.

Higher plasma prorenin concentration plays a role in the development of coronary artery disease.

BackgroundProrenin and renin are both involved in atherosclerosis. However, the role of plasma prorenin and renin in the development and progression of coronary artery disease (CAD) is still not clear. Thus, we aimed to examine the relationships among plasma prorenin concentration, CAD and clinical parameters.MethodsWe measured plasma prorenin and renin concentrations and other parameters in 85 patients who underwent coronary angiography. Patients were divided into a CAD group (≥75 % stenosis in one or more coronary arteries) and a non-CAD group.ResultsThere was a weak correlation between prorenin and plasma renin concentration (r =0.35, p =0.001), and plasma renin activity (r =0.34, p =0.001). There was no significant difference in the plasma prorenin concentration between the CAD group and non-CAD group. However, patients with a high plasma prorenin concentration frequently suffered CAD. Receiver-operating-characteristic curve analysis showed that the optimal cutoff value of plasma prorenin concentration to detect CAD was 1,100 pg/ml, with a positive predictive value of 94 % and a negative predictive value of 36 %.ConclusionThe plasma prorenin concentration increases with increases in plasma renin concentration. Higher plasma prorenin concentration (>1,100 pg/ml) plays a role in the development of CAD.

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Objectives 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 plasma prorenin concentrations during pregnancy, and we assessed the incidence of pregnancy-induced hypertension. Methods We measured plasma prorenin concentrations in 430 pregnant women (565 samples). Regression analysis was performed to determine the associations between the plasma prorenin level and maternal/neonatal complications. Results The plasma prorenin concentration and gestational age had a positive correlation in non-pregnancy-induced hypertension in women with singleton pregnancies (Spearman rank-correlation coefficient, −0.215; p p p = 0.0107). Conclusions The plasma 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. Disclosures Y. Mikami: None. T. Narita: None. Y. Takai: None. K. Baba: None. H. Seki: None. K. Matsuoka: None.

Response to "Is High Prorenin Level Related to Relative Aldosterone Excess?"

To the Editor: We would like to thank Dr. Satoh and colleagues for their interest in our recent study titled “Plasma Levels of Prorenin and Renin in Black and Whites: Their Relative Abundance and Associations with Plasma Aldosterone Concentration.”1 We reported that blacks and whites had similar plasma prorenin levels, but that in blacks the plasma renin concentration (PRC) was markedly lower, and prorenin was negatively associated with plasma aldosterone concentration (PAC). In their Letter to the Editor, Dr. Satoh suggested we should further examine the association between prorenin and aldosterone to plasma renin activity ratio (aldosterone/renin ratio, or ARR), for indication that prorenin might have played a role in the relative excess of aldosterone, especially in blacks, who are thought to be more susceptible to a salt-sensitive form of hypertension. We appreciate this suggestion and agree that this is a logical and potentially important question that should be addressed in a follow-up analysis. We reexamined the data as requested. The relationships between prorenin and ARR are presented in Figure 1. Contrary to the letter’s hypothesis, we found prorenin to be negatively associated with ARR in blacks (β = –0.341; P = 0.039), and not associated with ARR in whites (β = 0.180; P = 0.301). Of note, these results essentially mirrored our previous reports on the prorenin-PAC relationships in the two race groups. Careful examination of Figure 1c and Figure 1d of the original report revealed that at any given level of PRC, prorenin was negatively associated with PAC in blacks, and positively associated with PAC in whites. The new analysis reaffirmed this observation. Figure 1. Relationship between plasma prorenin concentration and plasma aldosterone to renin activity ratio in blacks and whites. Abbreviations: PAC, plasma aldosterone concentration; PRA, plasma renin activity. We agree with Dr. Satoh and colleagues that ARR is a useful gauge for salt sensitivity, characterized by inappropriate aldosterone production and unattenuated sodium reabsorption in the presence of volume overload. Previous reports have demonstrated that ARR is higher in hypertensive blacks than in hypertensive whites.2 Our data, showing that ARR levels were marginally higher in young and normotensive blacks (Table 2 of the original paper), suggest that this difference may already be present before hypertension occurs. The new analysis, however, yielded no clear evidence for a prorenin role in aldosterone production, neither in blacks nor whites. In fact, the negative prorenin-ARR association in blacks argues against the hypothesis that prorenin promotes aldosterone production, at least in young and healthy blacks. As we have commented in the original article, this does not exclude the possibility that in some circumstances aldosterone production may become more autonomous to kidney-derived renin; when upregulated (pro)renin receptor (PRR) expression leads to a prorenin-dependent generation of angiotensin II, it is conceivable that aldosterone excess may occur with increased prorenin levels. Although the plausibility of such a hypothesis is supported by the observations that aldosterone elevation is associated with the PRR overexpression in transgenic rats and PRR gene polymorphisms in white males,3,4 the validity of the hypothesis in salt-sensitive blacks remains to be investigated.

Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism

The aim of the present study was to test the hypothesis that elevation of prorenin in plasma is sufficient to induce cardiac fibrosis. Normotensive cyp1a1ren-2 transgenic rats with normal plasma prorenin and aldosterone levels were given 0.125% indole-3-carbinol (I3C) orally for a period of 12 wk. Plasma prorenin and aldosterone levels were determined in 4-wk intervals, and cardiac marker enzymes for hypertrophy, fibrosis, and oxidative stress as well as cardiac pathology were investigated. In I3C-treated cyp1a1 ren-2 transgenic rats, plasma prorenin concentrations were >100-fold elevated (≥7.1 ± 2.6 μg ANG I·ml−1·h−1 vs. ≤0.07 ± 0.1; P < 0.001), whereas active renin levels were suppressed (0.09 ± 0.02 vs. 0.2 ± 0.1; P < 0.05). Aldosterone concentrations were elevated three- to fourfold for a period of >4 wk (574 ± 51 vs. 160 ± 68 pg/ml; P < 0.01). After 12 wk of I3C, rats exhibited moderate cardiac hypertrophy (heart weight/body weight 2.5 ± 0.04 vs. 3.1 ± 0.1 mg/g; P < 0.01). There was a slight increase in mRNA contents of endothelin 1 (1.21 ± 0.08 vs. 0.75 ± 0.007; P < 0.001), NADP oxidase-2 (1.03 ± 0.006 vs. 0.76 ± 0.04; P < 0.001), transforming growth factor-β (0.99 ± 0.06 vs. 0.84 ± 0.04; P < 0.05), collagen type I (1.32 ± 0.32 vs. 0.94 ± 0.18; P < 0.05), and intercellular adhesion molecule-1 (1.12 ± 0.12 vs. 0.84 ± 0.08; P < 0.05). These genes are known to be stimulated by the renin-angiotensin system. There were no histological signs of fibrosis in the heart. We found that prorenin and aldosterone alone are not sufficient to induce considerable cardiac fibrosis in the absence of sodium load.

(Pro)renin Receptor: A Treatment Target for Diabetic Retinopathy?

Many lines of evidence implicate the renin-angiotensin system in the pathogenesis of diabetic retinopathy. A recent multicenter trial showed that angiotensin II type 1 (AT1) receptor blockade (ARB) reduced the incidence of retinopathy in type 1 diabetic patients and improved the regression of retinal disease in type 2 diabetic patients (1,2). However, the failure of ARB to prevent progression of diabetic retinopathy indicates a role for mechanisms additional to angiotensin II in its pathogenesis. In this issue of Diabetes , Satofuka et al. (3) provide evidence that prorenin and the (pro)renin receptor, acting in part through mechanisms unrelated to angiotensin II, may contribute to the pathogenesis of diabetic retinopathy. This evidence holds promise for new therapies for diabetic retinopathy and other complications of diabetes. Prorenin is a high–molecular weight biosynthetic precursor of renin. It has a low intrinsic activity of <2% of the activity of renin (4) because it has an amino-terminal 43–amino acid prosegment that masks the active site, thereby preventing access by the renin substrate—angiotensinogen. Renal juxtaglomerular cells are the only known site of renin production, whereas the kidney and a number of extrarenal tissues including adrenal, ovary, testis, placenta, and retina produce prorenin (5–7). Plasma prorenin concentrations are ∼10- to 20-fold higher than those of renin (4). Prorenin concentrations in plasma and vitreous fluid are increased in diabetic subjects (6,8), and plasma prorenin is a powerful marker for both prevalent and incident microvascular complications of diabetes, including nephropathy, retinopathy, and …

Plasma and Renal Renin Concentrations in Adult Sheep After Prenatal Betamethasone Exposure

This study examined whether renin expression and secretion and plasma angiotensin II (Ang II) levels were altered in adult sheep exposed to antenatal betamethasone. Pregnant sheep received injections of 0.17 mg/kg betamethasone or vehicle, at 80 and 81 days of gestation, and offspring were studied at 6 and 18 months of age. At 6 months, plasma prorenin concentrations were significantly lower in betamethasone animals (4.63 +/- 0.64 vs 7.09 +/- 0.83 ng angiotensin I/mL/h, P < .01). The percentage of plasma active renin was significantly higher in the betamethasone group (31.93 +/- 4.09% vs 18.57 +/- 2.79%, P < .01). Plasma and renocortical renin levels were similar in both groups at 18 months, but plasma renin activity was lower than at 6 months. Ang II levels were suppressed by betamethasone. The data indicate that prenatal exposure to betamethasone alters processing and secretion of renin in offspring at 6 months, but that this difference is not apparent at 18 months.

Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis

Prorenin has been associated with cardiovascular disease and the development of glomerulosclerosis via a renin/prorenin receptor. In cyp1a1ren-2 transgenic rats, prorenin levels and arterial pressure can be increased by oral administration of indole-3-carbinol (I3C). The transgenic strain has been used as a model of malignant hypertension. The present study was designed to test the hypotheses that (i) low doses of I3C would result in dose-dependent sustained increases in arterial pressure without signs of malignancy, making cyp1a1ren-2 transgenic rats a useful model to study nonmalignant hypertension, and (ii) cyp1a1ren-2 transgenic rats would develop glomerulosclerosis when they were chronically exposed to 0.125% I3C in their diet. I3C treatment for 2 weeks resulted in increases of plasma prorenin concentrations and arterial pressure in a dose-dependent manner. Rats thrived well over a period of 12 weeks on dietary I3C concentrations (wt/wt) of 0.125%. Plasma prorenin concentration rose from 0.1 +/- 0.1 microg to 17.9 +/- 5.0 mug angiotensin I/ml per h (P < 0.01) and mean arterial pressure increased to a plateau of 170 +/- 5 mmHg (P < 0.001) between weeks 6 and 12. After 12 weeks of 0.125% I3C, rats exhibited moderate hypertensive renal vasculopathy, but no histological signs of glomerulosclerosis. The cyp1a1ren-2 transgenic rat model allows for chronic dose-dependent titration of arterial pressure by a simple and non-invasive intervention, making this strain a useful model to study malignant and nonmalignant arterial hypertension. High circulating prorenin levels per se do not cause glomerulosclerosis.

Prorenin and Angiotensin-Dependent Renal Vasoconstriction in Type 1 and Type 2 Diabetes

Prorenin is a powerful marker for risk of nephropathy and retinopathy in diabetes, but the responsible mechanism remains unclear. Studied were 35 patients with diabetes (18 with type 1 and 17 with type 2) and 69 age-matched healthy subjects with para-aminohippurate and inulin clearances and their response to captopril. All patients with diabetes had normal renal function and no microalbuminuria. Prorenin was calculated as the difference between total renin and active renin. Active renin level in patients with diabetes (11.6 +/- 0.9 microU/ml) was significantly lower than in normal subjects (14.5 +/- 1.3 microU/ml; P < 0.05); despite this, the renal vascular response to captopril was much larger (82.9 +/- 11.5 versus 13.6 +/- 5.8 ml/min per 1.73 m(2); P < 0.01). Prorenin in both patients with type 1 and type 2 diabetes (175.7 +/- 15.1 microU/ml) also was significantly higher than in normal subjects (128 +/- 5.8 microU/ml; P < 0.01). Active renin correlated with prorenin in normal subjects (r = 0.44, P = 0.0002), and this correlation was much more striking in patients with diabetes (r = 0.72, P = 0.0001). The active renin and prorenin correlation was identical in type 1 and type 2 diabetes. There was a clear correlation between plasma prorenin and the renovascular response to captopril in patients with diabetes (P < 0.01) but not in normal subjects (P > 0.13). The strong correlation between plasma prorenin concentration and the renovascular response to captopril in diabetes supports the hypothesis of a direct effect of prorenin, but the unanticipated high degree of correlation between plasma prorenin and active renin limits the conclusions that can be drawn.

Laughter therapy modulates the parameters of renin-angiotensin system in patients with type 2 diabetes

The effect of laughter therapy on the plasma levels of renin, angiotensinogen, and prorenin was investigated in patients with type 2 diabetes. In the diabetic patients, the mean plasma renin concentrations were 24.6+/-12.1 ng/ml/h in the first observation (at the beginning of laughter therapy), 8.2+/-3.4 ng/ml/h in the second observation (three months after the beginning of laughter therapy) and 7.7+/-1.7 ng/ml/h in the third observation (six months after the beginning of laughter therapy). The mean plasma angiotensinogen concentrations in the 1st, 2nd and 3rd observations were 0.19+/-0.08, 0.47+/-0.12, 0.42+/-0.14 microg/ml, respectively. The mean plasma prorenin concentrations in the 1st, 2nd and 3rd observations during the laughter therapy were 195.1+/-66.2, 193.4+/-88.2 and 170.7+/-52.5 pg/ml, respectively. Plasma renin concentrations were significantly decreased (p<0.05) by the therapy. Subnormal concentrations of plasma angiotensinogen were found in the 1st observation and increased significantly (p<0.05) to the normal range after the therapy. Plasma prorenin concentration only slightly changed during the laughter therapy. Other biochemical parameters remained unchanged during the laughter therapy. These results indicated that a long-term laughter therapy changed the plasma components of renin-angiotensin system in patients with diabetes. Thus, laughter therapy can be used as non-pharmacological treatment for the prevention of diabetic microvascular complications.

Uterine arterial blood flow and the substances of ovarian renin–angiotensin system in women with polycystic ovaries undergoing in vitro fertilization

Objective To find whether plasma and follicular prorenin concentrations have any effect on the uterine arterial blood flow in women with polycystic ovarian syndrome (PCOS) compared to those with normal menstrual cycles (NMC). Study design Controlled prospective clinical study involved 55 women undergoing in vitro fertilization: 24 with PCOS and 31 with NMC. In both groups transvaginal colour Doppler assessment of uterine arterial blood flow was analysed on day 22 of the cycle, on the day of human chorionic gonadotrophin (HCG) administration and 36 h after HCG. Plasma and follicular (in the dominant follicle containing mature oocyte, and in the pooled follicles) prorenin and active renin, and serum estradiol and androstenedione concentrations were measured at these time-points. The Student's t-test and Pearson correlation were used for the statistical analysis. Results The resistance index (RI) in the NMC group decreased from 0.84 ± 0.05 on the day of HCG to 0.78 ± 0.08 36 h after HCG ( P < 0.05); in the PCOS group the RI did not decrease. Follicular prorenin concentrations in the dominant follicle and in the pooled follicles were lower in the PCOS than in the NMC group (20,210 ± 10,831 μU/l, 16,753 ± 8634 μU/l versus 42,637 ± 35,400 μU/l, 33,067 ± 26,200 μU/l; P < 0.05). Conclusions Plasma prorenin concentrations do not affect vascular impedance to the uterine artery, but follicular prorenin do by newly formed low resistant vessels in the follicles.

Follicular fluid renin concentration in patients with polycystic ovaries treated with gonadotrophins in an in vitro fertilisation programme.

The initial hypothesis was that the follicular fluid prorenin concentration was higher in women with polycystic ovaries (PCO) compared to normally cycling women stimulated by gonadotrophins. In a controlled prospective study, 47 women undergoing in vitro fertilisation (IVF) were enrolled: 20 women with PCO represented the study group and 27 normally cycling women the control group. Plasma prorenin, active renin, serum oestradiol, and androstenedione concentrations were measured on the day of human chorionic gonadotrophin (HCG) administration and 36 hours after HCG administration. Follicular fluid prorenin, active renin, oestradiol, and androstenedione concentrations from the dominant follicle and pooled follicles were measured 36 hours after HCG administration. Plasma prorenin concentration 36 hours after HCG administration was significantly higher in the PCO group (1867 microU/l; range 1137-3162 microU/l) than in controls (860 microU/l; range 433-1763 microU/l) (p = 0.007). The follicular fluid prorenin concentration in the dominant follicle and in the pooled follicles was lower in the PCO group (20190 microU/l; range 11130-25955 microU/l) than in controls (46930 microU/l; range 20671-66171 microU/l) (p = 0.003). We conclude that plasma prorenin concentrations in gonadotrophin-stimulated PCO cycles are augmented due to numerous follicles. Lower follicular fluid prorenin concentrations in women with PCO show that the synthesis of prorenin in theca cells starts later after HCG administration than in normally cycling women.

PRORENIN CONCENTRATION IN THE HYPERTENSIVE DISORDERS IN PREGNANCY

Objective: To evaluate the plasma prorenin levels during the three trimesters of normal pregnancy, their prognostic value, and their correlation with hypertensive disorders of pregnancy.Design: A prospective study in which plasma prorenin and renin levels were measured in 55 healthy pregnant women and 66 who developed gestational hypertension or preeclampsia. The patients were classified as mild preeclampsia (mild PE), severe preeclampsia (severe PE), chronic hypertension and superimposed preeclampsia upon chronic hypertension (superimposed PE).Method: Venous blood samples were collected in the first, second and third trimesters and during delivery or cesarean. Plasma renin concentration (PRC) was measured by radioinmmunoassay before and after incubation with trypsin solution. The difference gave plasma prorenin concentration (PProRC).Results: PRC and PProRC were significantly higher in pregnant women compared with healthy non-pregnant. PRC was significantly increased in the first trimester in the chronic hypertension group and a lower value was found in the first trimester in the superimposed PE compared with those in healthy pregnant women. No differences in other groups were found. PProRC showed a significant lower value in the first and third trimesters in the severe PE group. In the superimposed PE a low value of PProRC similar to those of non-pregnant women was found.Conclusions: The results show that the different types of hypertension in pregnancy have different profiles of PProRC and PRC in relation to development of preeclampsia. The absence of increase of PProRC in the first trimester of superimposed PE may have a prognostic value.

High plasma concentrations of prorenin in a transgenic animal model of nephropathy with overexpression of transforming growth factor-beta1 in the kidneys.

1. Plasma concentrations of prorenin were determined in a transgenic animal model of nephropathy induced by overexpression of transforming growth factor (TGF)-beta1 in the juxtaglomerular apparatus. 2. In both female and male mice, plasma concentrations of prorenin were higher in transgenic than in non-transgenic animals. In sexually mature mice, plasma prorenin concentrations were higher in males than in females in both transgenic and non-transgenic animals in accordance with a sexual dimorphism of the plasma concentration of prorenin. 3. The results indicate that TGF-beta1-like androgens increase prorenin secretion in the kidneys and may explain the increased plasma prorenin concentrations in patients with diabetic nephropathy.

Active renin, prorenin, and renin gene expression after reduced renal perfusion pressure in term ovine fetuses.

We studied the pattern of plasma active renin concentration (ARC), prorenin concentration (PRC), renal renin concentration, and the renin mRNA levels in ovine fetuses subjected for 24 h to reduced renal perfusion pressure (RPP). The results obtained in five animals (133.8 +/- 1.4 days of gestation) in which RPP was reduced by 10 mmHg were compared with those in seven control fetuses (130.3 +/- 0. 8 days of gestation) without pressure reduction. Plasma samples were obtained before and at intervals of 24 h after initiating reduced RPP. The plasma ARC increased within 60 min of reduced RPP, reaching a maximum (13.0 +/- 4.7 vs. 115.7 +/- 23.8, P < 0.01) at 3 h. The ARC then declined toward control values. In contrast, plasma PRC did not increase consistently until 4 h into reduced RPP, with maximal levels at 24 h (8.2 +/- 2.4 vs. 87.7 +/- 21.9, P = 0.016). Within the kidney PRC, but not ARC, increased significantly, by 2.5-fold. Reduced RPP also increased renal renin mRNA levels (P = 0.004). We conclude that a chronic reduction in RPP in the near-term ovine fetus increases renal PRC and is associated with increased plasma prorenin levels. The data suggest that the conversion of prorenin to active renin is an important regulation point of the renin ANG system during development.

Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

We have developed a transgenic animal model to investigate the effects of overexpression of rat prorenin on the cardiovascular system. Two transgenic rat lines were generated in which rat prorenin expression was directed to the liver by a human alpha1-antitrypsin promoter. Liver-specific expression was confirmed by RNase protection assay. Plasma prorenin concentrations in transgenic rats were increased 400-fold in the males of both lines but were increased only two- to threefold in the females. Thus, transgene expression exhibited sexual dimorphism. Blood pressures were not significantly higher in transgenic rats than in nontransgenic controls. The ratio of heart weight to body weight was greater in male transgenic rats than in the nontransgenic controls. Histological analysis revealed severe renal lesions and hypertrophic cardiomyocytes in transgenic males only. This transgenic model demonstrates a likely role of prorenin in the development of cardiac and renal pathology independent of hypertension. These animals will facilitate studies of the effects of blockade of the renin-angiotensin system and other pharmacological interventions on the development and treatment of cardiac, vascular, and renal lesions induced by changes in this system in the absence of chronic hypertension.

Relationship between prorenin, IGF-I, IGF-binding proteins and retinopathy in diabetic patients

Plasma prorenin and renin, serum insulin-like growth factor I (IGF-I) and IGF-binding protein (IGFBP-2 and IGFBP-3) concentrations were measured in 22 randomly selected male and female patients with insulin-dependent diabetes mellitus (IDDM) or non-IDDM (NIDDM). Plasma prorenin concentration was significantly elevated in patients with proliferative retinopathy (1869.5±785.0 mUL −1, mean±SEM) compared to patients with nonproliferative retinopathy (325.5±73.2 mUL −1, P<0.003) and those without retinopathy (318.6±47.3 mUL −1, P<0.007). Similarly, serum insulin-like growth factor-I (IGF-I) concentration in patients with proliferative retinopathy (216.3±21.5 μgL −1) was significantly higher than in patients with nonproliferative retinopathy (126.3±14.85 μgL −1, P<0.004) and without retinopathy (135.2±37.26, P<0.05). There was moderately strong positive correlation between plasma prorenin and serum IGF-I concentrations ( r=0.56, P<0.01). Plasma prorenin concentration was uninfluenced by change in renal function (creatinine clearance, serum creatinine or BUN), but IGF-I levels were inversely related to creatinine clearance ( r=0.67, P<0.002). There was no demonstrable relationship between IGF-binding proteins and prorenin or renin concentrations. In view of some overlap between plasma prorenin and serum IGF-I concentrations in diabetic patients with proliferative and nonproliferative retinopathy, measurement of both markers may be more useful in prédicting the development of proliferative retinopathy in patients with diabetes mellitus than either measurement alone.