Total Plasma Renin Research Articles

Renin-Angiotensin-Aldosterone System Activation and Diuretic Response in Ambulatory Patients With Heart Failure

Rationale & ObjectiveHeart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the association of renin-angiotensin-aldosterone system (RAAS) activation with diuretic response.Study DesignObservational cohort.Setting & PopulationEuvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment.PredictorsPlasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels.OutcomesSodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose.Analytical ApproachRobust linear regression models estimated the associations of each RAAS intermediate with outcomes.ResultsThe analysis included 56 participants, and the median age was 65 years; 50% were women, and 41% were Black. The median home diuretic dose was 80-mg furosemide equivalents. In unadjusted and multivariable-adjusted models, higher levels of RAAS measures were generally associated with lower diuretic efficiency. Higher plasma total renin remained significantly associated with lower sodium output per doubling of diuretic dose (β = −0.41 [−0.76, −0.059] per SD change) with adjustment; higher plasma total and active renin were significantly associated with lower fractional excretion of sodium per doubling of diuretic dose (β = −0.48 [−0.83, −0.14] and β = −0.51 [−0.95, −0.08], respectively) in adjusted models. Stratification by RAAS inhibitor use did not substantially alter these associations.LimitationsSmall sample size; highly selected participants; associations may not be causal.ConclusionsAmong multiple measures of RAAS activation, higher plasma total and active renin levels were consistently associated with lower diuretic response. These findings highlight the potential drivers of diuretic resistance and underscore the need for high-quality trials of decongestive therapy enhanced by RAAS blockade.

Maintaining Normal Blood Pressure in a Renovascular Stenosis Model of Hypertension in Adult Lewis Rats: Putative Physiological Modulation of the Renin‐Angiotensin System

Prolonged unilateral renal artery stenosis using a Goldblatt Two-Kidney-One Clip (2K1C) technique is a validated scientific approach to inducing experimental hypertension in laboratory animals. This patho-physiological modulation is associated with the activation of the renin-angiotensin system with increased renin and angiotensin II release to initiate hypertension. This mode of experimental hypertension has been demonstrated for many rat strains including Sprague Dawley, Brown Norway and Wistar Kyoto but has not been fully characterized in syngeneic Lewis rats. The objective of this study was to develop and characterize a unilateral renal artery stenosis model of hypertension in adult male Lewis rats using a 2K1C method for hypertension studies in our laboratory. Thirty animals were randomly assigned to two groups to undergo sham or the 2K1C surgical procedure under isoflurane-induced anesthesia; approval was granted by our institutional animal ethics committee (A2404, n =15 per group). Hemodynamic parameters including heart rate; systolic and diastolic blood pressure were monitored weekly for 6 weeks, using a volume-pressure tail cuff and a CODA pressure computer. Plasma concentrations of critical biomarkers of the renin-angiotensin system were quantified using standard ELISA assays and renal histopathological changes were assessed microscopically. Unilateral renal arterial stenosis caused marked renal atrophy, glomerulosclerosis and interstitial fibrosis, but a compensatory renal hypertrophy was observed in contralateral kidneys. Interestingly, unilateral renal arterial stenosis failed to induce hypertension over the six week period. The resistance to develop hypertension in the 2K1C group was associated with a significant decrease in total plasma renin (P = 0.023), an increase in the ratio of plasma angiotensin (1-7) to total renin (P = 0.034) and a decrease in the ratio of angiotensin II to total renin (P = 0.013). There were no changes in plasma electrolytes, glucose, creatinine or urea. These data demonstrate that adult male Lewis rats may have physiologically modulated the activation of the renin-angiotensin system to maintain a homeostatic balance and resist hypertension following unilateral renal artery stenosis.

The Effects of Two Intervention Strategies to Reduce the Intake of Salt and the Sodium-To-Potassium Ratio on Cardiovascular Risk Factors. A 4-Month Randomised Controlled Study among Healthy Families

The aim was to examine the effects of two different salt reduction strategies on selected cardiovascular risk factors. The study was a four-month cluster randomised controlled study. Eighty-nine healthy Danish families (309 individuals) were randomly assigned to either (A) gradually salt-reduced bread, (B) gradually salt-reduced bread and dietary counselling to further reduce salt intake and increase potassium intake or (C) standard bread (control). The effect was assessed using linear mixed models. Intention to treat analyses comparing changes in the three groups showed a significant reduction in body fat percent (−1.31% (−2.40; −0.23)) and a borderline significant reduction in total plasma cholesterol (−0.25 mmol/L (−0.51; 0.01) and plasma renin (−0.19 pmol/L (−0.39; 0.00) in group A compared to the control group. Adjusted complete case analyses showed a significant reduction in total plasma cholesterol (−0.29 mmol/L (−0.50; −0.08), plasma LDL cholesterol (−0.08 mmol/L (−0.15; −0.00)), plasma renin (−0.23 pmol/L (−0.41; −0.05)), plasma adrenaline (−0.03 nmol/L (−0.06; −0.01)) and body fat percent (−1.53% (−2.51; −0.54)) in group A compared to the control group. No significant changes were found in group B compared to the control group. In conclusion, receiving sodium reduce bread was associated with beneficial changes in cardiovascular risk factors. No adverse effects were observed.

PCSK9 in diabetic kidney disease.

Chronic Kidney Disease (CKD) and, specifically, diabetic kidney disease (DKD)+, is among the fastest increasing causes of death worldwide. A better understanding of the factors contributing to the high mortality may help design novel monitoring and therapeutic approaches, since protection offered by statins in CKD patients is not satisfactory. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes hypercholesterolemia and may be targeted therapeutically. Adding anti-PCSK9 agents to standard lipid lowering therapy further reduces the incidence of cardiovascular events. We studied plasma PCSK9 in a cross-sectional study of 134 diabetic kidney disease patients with estimated glomerular filtration rate (eGFR) categories G1-G4 and albuminuria categories A1-A3, in order to identify factors influencing plasma PCSK9 in this population. Mean±SD plasma PCSK9 levels were 309.8±113.9 ng/ml. Plasma PCSK9 was not influenced by eGFR or albuminuria, but was higher in patients on lipid lowering therapy. In univariate analysis, plasma PCSK9 showed a significant positive correlation with serum total iron binding capacity, vitamin E, plasma renin and phosphaturia, and there was a trend towards a positive correlation with total serum cholesterol. In multivariate models, only therapy with fibrate and statin, and renin remained independently correlated with plasma PCSK9. However, multivariate models explained very little of the PCSK9 variability. In DKD, therapy with lipid lowering drugs and specially the fibrate/statin combination were independently associated with higher PCSK9 levels. The biomarker potential of PCSK9 levels to identify DKD patients that may benefit from anti-PCSK9 strategies should be studied.

Blood pressure changes after catheter-based renal denervation are related to reductions in total peripheral resistance.

Renal denervation (RDN) can reduce sympathetic activity and blood pressure (BP) in patients with uncontrolled hypertension. The exact mechanisms by which RDN results in BP reductions are yet not fully established. This study investigated the effects of RDN on office BP, 24-h ambulatory BP, noninvasive 10-min beat-to-beat digital pulse wave analysis, total peripheral resistance (TPR), cardiac output, and plasma renin and aldosterone serum concentrations in 30 patients with resistant hypertension. Adherence to antihypertensive drugs was assessed by liquid chromatography high-resolution tandem mass spectrometry analysis in plasma and urine at baseline and at 6 month. RDN significantly reduced office BP, beat-to-beat BP, and 24-h ambulatory BP by 19/6 (P = 0.021/P = 0.012), 12/7 (P = 0.005/P = 0.005), and 10/5 mmHg (P = 0.001/P = 0.049) at 6 months, respectively. TPR decreased from 1696 to 1377 dyn × s/cm (-19%; P = 0.027). This reduction was not associated with significant changes in cardiac output. The changes in office, ambulatory, and beat-to-beat BP correlated with the reductions of TPR. Adherence to antihypertensive treatment remained unchanged during the study period (84.7% at baseline, 83.6% at 6 months, P = 0.782). RDN reduced office BP, beat-to-beat BP, and 24-h ambulatory BP in patients with resistant hypertension after 6 months. The BP changes were associated with reductions in peripheral resistance, whereas cardiac output, plasma renin, and aldosterone levels remained unchanged. The observed effects were not explained by an increased intake of antihypertensive medications.

Maternal insulin-like growth factor 1 and 2 differentially affect the renin–angiotensin system during pregnancy in the guinea pig

ObjectiveInsulin-like growth factors (IGFs) are known to interact with the renin–angiotensin system (RAS). We previously demonstrated that administration of IGF1 to guinea pigs in early to mid pregnancy promotes placental function and fetal growth in mid to late gestation. Early administration of IGF2 had sustained, but not acute, effects on these parameters and also on placental structural differentiation. Here, we aimed to determine whether the IGFs interact with the placental RAS in early to mid gestation to modulate placental development and increase fetal growth and survival, and if IGF2 binding the IGF2R is implicated in the sustained effects of IGF2 treatment. DesignAt day 20 of pregnancy, guinea pigs were infused with 1mg/kg/day of IGF1, IGF2, Leu27IGF2 or vehicle for 18days and sacrificed on either day 62 (late pregnancy) or during the infusion period on day 35 (early–mid pregnancy). Placental structure at day 35 was analyzed using morphometric technique and expression of RAS genes in the placenta and placental and plasma renin activity were measured at both time points. ResultsCompared with vehicle at day 35 of gestation, IGF1 infusion reduced the total midsagittal cross-sectional area of the placenta (−17%, p=0.02) and the labyrinth area (−22%, p=0.014) but did not alter the labyrinth volume nor labyrinth:interlobium ratios. IGF2 treatment did not affect placental structure.IGF1 did not alter placental mRNA for any of the RAS genes quantified at day 35 (AGTR1, ACE, AGT, TGFB1) but increased TGFB1 expression by more than 16-fold (p=0.005) at day 62. IGF2 increased placental expression of AGTR1 (+88%, p=0.03) and decreased AGT (−73%, p=0.01) compared with the vehicle-treated group at day 35, and both IGF2 and Leu27IGF2 increased expression of TGFB1 at day 62 by 9-fold (p=0.016) and 6-fold (p=0.019) respectively.Both IGFs increased the ratio of active:total placental renin protein (+22% p=0.026 p=0.038) compared to vehicle compared to vehicle at day 35 but not 62. At day 62, IGF2-treated mothers showed a marked increase in total plasma renin (+495%) and active renin (+359%) compared to vehicle but decreased the ratio of active to total renin by 41% (p=0.042). Leu27IGF2-treated animals had higher levels of placental active renin (+73%, p=0.001) and total renin (+71%, p=0.001) compared with the vehicle control. ConclusionsThe data obtained in the current study suggest the potential for alternate roles for the induction of the RAS after IGF treatment. IGF1 and 2 treatments increase the activation of prorenin to renin in the placenta, possibly due to increased protease activity. In addition, IGF2 treatment in early pregnancy may enhance the maternal adaptation to pregnancy through stimulation of renin in the kidney. The sustained effects on placental differentiation and function after IGF2 treatment suggest therapeutic potential for exogenous administration of IGFs in improving pregnancy outcomes.

COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla.

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

Predictors of large volume paracantesis induced circulatory dysfunction in patients with massive hepatic ascites

Purpose:In patients with massive ascites, large volume paracentesis may be associated with complications as circulatory dysfunction. Selection of appropriate patients might reduce such side effects.Patients and Methods:Forty-five patients known to have liver cirrhosis and presenting with massive ascites were included. There were 27 males and 18 females, with age (mean 51.2+10.64). All patients were subjected to full history, clinical examination, complete blood picture, prothrombin time, serum albumin, total plasma protein, serum bilirubin, serum creatinine, serum electrolytes and plasma renin activity measured by radioimmunoassay. Echocardiographic evaluation for cardiac output, pulmonary artery pressure, diastolic and systolic function before and after paracentesis. Large-volume paracentesis (LVP) ranging 8–18 liters with a mean 9.9 L was performed to all patients. Paracentesis induced circulatory dysfunction (PICD) was defined as increase in plasma renin activity (PRA) of more than 50% of pretreatment value to a level greater than 7.5ng /ml/ hour on the 6th day after paracentesis.Results:The incidence of PICD in patients with massive hepatic ascites was 73.3% (87.5% with Dextran and 38.5% with albumin). There were no serious systemic or local side effects one week following LVP. Type of plasma expander and younger ages were the only independent predictors (odd ratio OR with 95% confidence interval CI, 3.01<21.79<157.58 and 0.80<.88<.97 respectively) Gender and other clinical and laboratory parameters had no influence. Neither electrolytes levels nor hematocrite value had an influence. Ascitic patients showed higher heart rate and cardiac output and lower arterial pressure that was accentuated after LVP (P < 0.01). Echocardiographic diastolic function, A wave velocity and deceleration time of the E wave were markedly increased in cirrhotic patients with tense ascites and the E/A ratio was markedly reduced (0.9 ± 0.3) but was not significantly affected by LVP. Ejection fraction had similar values of the normal patients with a tendency to increase after paracentesis. There were no changes in the left ventricular wall thickness.Conclusion:LVP is a safe and effective procedure for treatment of tense/refractory ascites. PICD is a frequently occurring silent complication following LVP. Salt free human albumin should be the plasma expander of choice especially if at least 8 liters are evacuated. Left ventricular diastolic function is altered in cirrhosis with tense ascites. This may represent an early stage of hepatic cardiomyopathy but was not affected by LVP and this was not reflected on the occurrence of PICD.

Hyperreninemia Characterizing Women with Polycystic Ovary Syndrome Improves after Metformin Therapy

Background: Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation, hyperandrogenemia and insulin resistance. Hyperreninemia is observed in insulin resistance and hyperandrogenemic states. Aims: To investigate the levels of total plasma renin and their possible relationship with insulin resistance and hyperandrogenemia and to explore the effect of metformin on these parameters in PCOS women. Methods: 48 PCOS women who were age- and body mass index (BMI)-matched with 21 healthy women were studied. Total renin, aldosterone levels, glucose and insulin levels were measured at basal state and during an oral glucose tolerance test in all subjects. A subgroup of women with PCOS was evaluated 6 months after metformin administration. Results: Total renin levels were significantly higher in PCOS women compared to controls. PCOS women compared to controls displayed higher areas under the curve for glucose, insulin and total renin (AUCREN). Mean AUCREN was correlated significantly with insulin resistance indices and positively with free testosterone levels. Total renin, aldosterone, androgen levels and insulin sensitivity indices were significantly improved after 6 months on metformin treatment. Conclusions: PCOS women demonstrated an insulin resistance and hyperandogenemia-related increase in serum total renin levels. Metformin treatment was shown to significantly reduce total renin levels.

Aldosterone and Metabolic Syndrome

The classic role of aldosterone is to regulate water and electrolyte balance and, therefore, blood pressure homeostasis.1 Apart from that, experimental studies have demonstrated that aldosterone induces structural and functional alterations in the heart, kidneys, and vessels with effects such as myocardial fibrosis, nephrosclerosis, vascular inflammation and remodeling, and disturbed fibrinolysis.2,3 This damage seems to be aldosterone mediated, and aldosterone blockade with mineralocorticoid receptor (MR) antagonists, such as spironolactone, may prevent the onset of these effects.4,5 On the other hand, it cannot completely be ruled out that potassium and high blood pressure also play additional key roles in this damage.6,7 This evidence has impressively been supported by clinical studies, such as the Randomized Aldactone Evaluation Study and the Eplerenone Post-Acute Myocardial Infarction Survival and Efficacy Study.8,9 For example, increased mortality in patients with chronic heart failure has been associated with elevated aldosterone plasma levels,10 and high circulating plasma aldosterone levels predict the clinical outcome in patients after myocardial infarction.11 Furthermore, primary aldosteronism (PA) has been demonstrated to enhance the risk of cardiovascular events12 and kidney disease.13 In summary, aldosterone is considered a cardiovascular risk factor, promoting disease processes such as cardiac fibrosis, nephrosclerosis, and arteriosclerosis,2,3,14 all of which are increased in patients with obesity and the metabolic syndrome.15,16 The term “metabolic syndrome” (MSyn) has evolved various definitions in recent times; most of the studies introduced here use slight modifications. Nevertheless, all of the definitions used have a common denominator, which is reflected in a definition by the American Heart Association/National Heart, Lung, and Blood Institute.17 According to this definition, the MSyn is considered as a constellation of interrelated risk factors of metabolic origin, including arterial hypertension, dyslipidemias, alterations in glucose homeostasis with type 2 diabetes mellitus, and abdominal …

Adenosine A 1 receptors determine effects of caffeine on total fluid intake but not caffeine appetite

Adenosine A 1 receptor wild-type (+/+) and knockout (−/−) mice were used to elucidate the role of adenosine A 1 receptors in caffeine self-administration in a two-bottle choice test and in the effect of caffeine on total fluid intake and plasma renin concentration. With access to water only, adenosine A 1 receptor −/− mice showed greater basal fluid intake and greater plasma renin concentration than +/+ mice. Free access to both water and a caffeinated solution (30 mg/100 ml) for 14 days increased total fluid intake only in adenosine A 1 receptor +/+ mice (by 23 ± 3%), and both total fluid intake and plasma renin concentration were no longer different between genotypes. Mean intake of water and caffeinated solution was not different between adenosine A 1 receptor +/+ and −/− mice. These data reveal that adenosine A 1 receptors do not contribute to caffeine consumption, but determine the effects of caffeine on fluid intake and plasma renin concentration.

Prolonged attenuation of cold-induced hypertension by adenoviral delivery of renin antisense

Renin has been linked to the pathogenesis of some forms of hypertension, including cold-induced hypertension (CIH). Although several antihypertensive drugs that inhibit angiotensin-converting enzyme (ACE) and angiotensin II (Ang II) type 1 (AT(1)) receptors are available, they are short-lasting and have side effects. Inhibition of renin [the first and rate-limiting step of the renin-angiotensin system (RAS)] would provide an inhibition of the entire RAS. Thus, we developed an antisense approach for specific inhibition of renin based on the genetic design. The objective of this study was to test our hypothesis that adenoviral delivery of renin antisense inhibits renin and attenuates CIH. Recombinant adenoviruses carrying rat renin antisense (rAdv.RRA) and LacZ reporter gene (rAdv.LacZ) were constructed and used for in vivo gene transfer via intravenous injection. Four groups of rats were used (six rats/group). Blood pressure did not differ among the four groups during the control period at room temperature (25 degrees C). Two groups of rats received rAdv.RRA (2.5 x 10(9) pfu/rat, intravenously), while the other two groups received the same dose of rAdv.LacZ and served as controls. After gene delivery, one rAdv.LacZ-treated and one rAdv.RRA-treated group were exposed to cold (5 degrees C), while the remaining groups were kept at 25 degrees C. Blood pressure was monitored weekly during cold exposure. A 24-hour urine sample was collected during weeks 1, 3, and 5 for measuring urinary aldosterone excretion. At the end of week 5, all animals were killed and blood was collected for measurement of plasma renin activity (PRA), total plasma renin, plasma active renin, and plasma aldosterone. Vascular Ang II contents were measured in all rats. Blood pressure of the rAdv.LacZ-treated group rose significantly within 2 weeks of exposure to cold and reached 158.2 +/- 6.4 mm Hg by week 5. In contrast, blood pressure (117.1 +/- 5.3 mm Hg) of the cold-exposed group treated with rAdv.RRA did not increase until 5 weeks after exposure to cold. Thus, a single dose of rAdv.RRA prevented CIH for at least 5 weeks. rAdv.RRA abolished the cold-induced increases in PRA, total plasma renin, plasma active renin, vascular Ang II, and plasma and urine aldosterone, indicating effective inhibition of the entire RAS. rAdv.RRA effectively inhibited the entire RAS and produced prolonged attenuation of CIH. Antisense inhibition of renin may be a novel and ideal approach for long-term control of hypertension.

Systemic arterial compliance in patients with high and low renin essential hypertension

The aim was to evaluate the systemic arterial compliance (SAC) in patients with essential arterial hypertension (AH) and different plasma total renin (PTR) levels. 29 patients with moderate to severe AH according to their plasma total renin level were divided in 2 groups: 1st -11 patients with PTR level > 400 ng/l; 2nd -18 patients with PTR level < 300 ng/l. Plasma renin concentration was measured by immunoradiometric assay with 2 monoclonal antibodies to active renin (plasma treated with trypsin). All patients were done carotid applanation tonometry. Patients of the 1st group characterized higher pulse blood pressure (68±6 vs 44 ±7 mm Hg, p < 0,05) and lower SAC (7,6 ± 0,8 vs 10,2 ± 0,7 ml/mmHg X 10, p < 0,05), but the same mean systolic and diastolic blood pressure (178 ±14,5/100 ± 7 vs 175 ±12,3/105 ± 14 mm Hg, NS) In spite of equal systolic and diastolic blood pressure levels patients with high PTR level had worse large artery mechanical properties, than patients with normal or low PTR level.

Influence of insulin resistance on total renin level in normotensive women with polycystic ovary syndrome

Objective: To evaluate the influence of insulin resistance on the plasma total renin level in normotensive women with polycystic ovary syndrome (PCOS). Design: Prospective, controlled study. Setting: University hospital. Patient(s): Twenty-five normotensive women with PCOS were compared with 11 normotensive control women with regular cycles and no features of PCOS. Intervention(s): Clinical, ultrasonographic, and hormonal findings were used to define PCOS. Insulin resistance was estimated by continuous infusion of glucose with model assessment in the early follicular phase. Main Outcome Measure(s): Plasma levels of total renin and angiotensin II and serum levels of gonadotropins, DHEAS, total T, free T, 17 α-hydroxyprogesterone, and PRL were determined. Result(s): Plasma concentrations of angiotensin II were similar in the PCOS group and the control group. The concentration of total renin in plasma was higher in women with PCOS than in healthy women independent of insulin resistance. The sensitivity and specificity of the plasma total renin level to diagnose women with PCOS were calculated as 80% and 71.4%, respectively. Conclusion(s): The plasma total renin level is higher in normotensive women with PCOS than in healthy women independent of insulin resistance.

Plasma renin and prorenin and renin gene variation in patients with insulin-dependent diabetes mellitus and nephropathy.

The most striking abnormality in the renin angiotensin system in diabetic nephropathy (DN) is increased plasma prorenin. Renin is thought to be low or normal in DN. In spite of altered (pro)renin regulation the renin gene has not been studied for contribution to the development of DN. We studied plasma renin, prorenin, and four polymorphic markers of the renin gene in 199 patients with IDDM and DN, and in 192 normoalbuminuric IDDM controls matched for age, sex, and duration of diabetes. Plasma renin and total renin were measured by immunoradiometric assays. Genotyping was PCR-based. Plasma renin was increased in patients with nephropathy (median (range), 26.3 (5.2-243.3) vs 18.3 (4.2-373.5) microU/ml in the normoalbuminuric group, P<0.0001). Prorenin levels were elevated out of proportion to renin levels in nephropathic patients (789 (88-5481) vs 302 (36-2226) microU/ml, P<0.0001). Proliferative retinopathy had an additive effect on plasma prorenin, but not on renin. DN was associated with a BglI RFLP in the first intron of the renin gene (bb-genotype: n=106 vs 82 in DN and normoalbuminuric patients respectively, P=0.037), but not with three other polymorphisms in the renin gene. A trend for association of higher prorenin levels with the DN-associated allele of this renin polymorphism was observed in a subgroup of patients with DN (bb vs Bb+BB, P=0.07). The results indicate that in DN there is an increase in both renin and prorenin levels. A renin gene polymorphism may contribute weakly to DN. Although speculative, one of the renin gene alleles could lead to increased renin gene expression, leading to higher renin and prorenin levels. These may play a role in the pathogenesis of DN.

β-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects

Although β-adrenergic–blocking drugs suppress the renin system (RAAS), plasma angiotensin II (Ang II) responses during β-blockade have not been defined. This study quantifies the effects of β-blockade on the RAAS and examines its impact on prorenin processing by measuring changes in the ratio of plasma renin activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16) subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and urinary aldosterone were measured before and after 1 week of β-blockade. Plasma renin activity, Ang II, and urinary aldosterone levels were similar for normotensive and hypertensive subjects. Plasma renin activity correlated with Ang II. Total renin, which is proportional to (pro)renin gene expression, was lower in hypertensive subjects and was inversely related to BP. β-Blockade decreased BP and heart rate in both groups, with medium- and high-renin hypertensive subjects responding more frequently than those with low renin. β-Blockade consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged, thus, %PRA fell. These results indicate that β-blockers suppress plasma angiotensin II levels, in parallel with the marked reductions in PRA and urinary aldosterone levels in normotensive and hypertensive subjects. The suppression of Ang II levels was comparable to that produced during angiotensin converting enzyme (ACE) inhibition. However, by reducing prorenin processing to renin, β-blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II receptor antagonists. This unique action of β-blockers has important implications for the treatment of cardiovascular disease.

Lipid metabolism alterations in normotensive subjects with positive family history of hypertension.

Metabolic abnormalities are usually reported in hypertensive patients. These metabolic alterations seem to begin in childhood. The young offspring of hypertensive parents have not been studied thoroughly for metabolic alterations. The aim of this study was to examine the level of total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, uric acid, glycemia, aldosterone, and plasma renin activity in a population of 42 young, slender normotensive subjects with positive family history of hypertension (FH+) or negative family history of hypertension (FH-). Measurements were made in 20 young normotensive subjects (age 21.1+/-2.2 years, 11 males, 15 white, 5 oriental, body mass index of 22.1+/-2.3 kg/m2) with FH+ and 22 young normotensive subjects (age 19.9+/-1.4 years, 17 males, 17 white, 5 oriental, body mass index of 22.1+/-2.3 kg/m2) with FH-. The total cholesterol (4.47+/-0.8 versus 3.95+/-0.6 mmol/L), LDL cholesterol (2.74+/-0.63 versus 2.36+/-0.61 mmol/L), VLDL cholesterol (0.5+/-0.25 versus 0.35+/-0.09 mmol/L), and triglycerides (2.52+/-1.26 versus 1.76+/-0.5 mmol/L) were significantly elevated (P<.05) in the FH+ group compared with the FH- group. The total cholesterol/HDL cholesterol ratio was significantly higher in the group with a positive family history of hypertension (3.75+/-0.02 versus 3.11+/-0.02, P<.05). Glycemia was slightly elevated in the FH+ group (2.16+/-0.29 mmol/L) but was not significantly different from that of the FH- group (2+/-0.2 mmol/L). Uric acid, plasma renin activity, and aldosterone were similar in both groups. We conclude that young, slender normotensive subjects with a positive history of hypertension show alterations in lipid metabolism, suggesting a positive correlation between lipid metabolism and hypertension heredity.

Renin, prorenin, and renin gene expression in rats with acute nephrotic syndrome.

1. The concentration of total, active and inactive renin was analysed in plasma, urine and kidney from control (C), pair-fed (PF) and nephrotic (NS) rats, as well as renin mRNA levels in kidney, liver and brain. 2. Nephrotic syndrome were induced by a single subcutaneous injection of puromycin aminonucleoside (PAN) and determinations were made 6 days after PAN injection. 3. Plasma total renin did not change, active renin increased in NS rats with respect to PF and C groups and in PF rats with respect to C. In contrast, the inactive renin percentage decreased in NS rats with respect to PF and C groups and in PF animals with respect to C. Total, active and inactive renal renin content did not change and active and inactive renin were significantly excreted by urine with no changes in the prorenin percentage with respect to C and PF groups. 4. In both NS and PF groups, renin mRNA levels did not change in any of the tissues studied. In another group of rats, kidney renin mRNA levels were measured on days 1, 3, 5 and 7 after PAN injection and no time-course changes in its expression were found. 5. These results suggest that renin gene expression is not altered in acute nephrotic syndrome and that plasma renin concentration is regulated at the translational or post-translational level in this experimental model.

EFFECT OF VITAMIN A ON CYCLOSPORINE NEPHROTOXICITY IN UNINEPHRECTOMIZED RATS

The influence of vitamin A (1.5 mg kg-1 body weight) administration for two weeks on cyclosporine A (CsA, 25 mg kg-1 body weight) induced renal dysfunction has been investigated in uninephrectomized and sham nephrectomized rats. Single kidney weight was significantly increased after uninephrectomy and CsA treatment. In addition CsA induced degenerative changes in renal tubule in uninephrectomized rats. The drug also significantly increased, serum total proteins, creatinine and plasma renin activity as well as urinary excretion of N-acetyl-β-D-glucosaminidase and 6-keto prostaglandin Fia. On the other hand, urine flow rate and creatinine clearance have been significantly reduced by CsA. Meanwhile no-significant change was observed on urinary prosta- glandin E2. Administration of vitamin A in combination with CsA reduced all abnormalities induced by CsA on Kidney strueture and functions. In conclusion vitamin A could be considered as an attenuating factor for CsA induced nephrotoxicity.

Plasma and renal prorenin/renin, renin mRNA, and blood pressure in Dahl salt-sensitive and salt-resistant rats.

We measured plasma prorenin and renin levels, renal renin mRNA, renal anti-renin and anti-prorenin-prosequence immunoreactivity, and blood pressure in maturing Brookhaven Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats during 14 days of low (0%), medium (0.4%), or high 4%) NaCl diets. Blood pressure was higher in Dahl S rats and did not increase with high NaCl. Seven-week-old Dahl R rats had twofold and sixfold higher levels of plasma prorenin and renal prosequence immunoreactivity, respectively, which by 9 weeks were the same as in Dahl S rats. The anti-renin antiserum, BR1-5, was found to detect prorenin better than renin; Dahl S rats had suppressed renal anti-renin immunoreactivity relative to Dahl-R rats. Dahl R rats were unresponsive to high NaCl, whereas in Dahl S rats, plasma renin and renal prosequence immunoreactivity fell by 90% (P < .01), renal anti-renin immunoreactivity and renal renin MRNA fell by 35% (P < .05 for both), and plasma prorenin fell by 30% (P = NS). NaCl depletion increased prorenin/renin parameters similarly in both strains. There were direct relationships among all of the prorenin/renin parameters. Between low and high salt diets in Dahl S rats, plasma renin increased 20-fold, plasma total renin (renin plus prorenin) and renal renin mRNA both increased threefold, and plasma prorenin increased twofold. The results indicate that under steady-state conditions, plasma and renal renin/prorenin parameters change concordantly and that plasma total renin (renin plus prorenin) reflects changes in renal renin mRNA. The lower blood pressure of Dahl R rats is associated with later maturation-related declines in plasma and renal prorenin. Suppression of plasma renin may delay the salt-induced blood pressure rise in Dahl S rats. Finally, the renin system and blood pressure of Dahl R rats have remarkable disregard for a high salt diet.