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PubMed1984

New monoclonal antibodies directed against human renin. Powerful tools for the investigation of the renin system.

Monoclonal antibodies directed against human renin were obtained by the fusing of myeloma cells with spleen cells from Balb/c or high-responder Biozzi mice injected with pure tumoral or highly purified renal renin. These procedures resulted in the production of seven stable monoclonal antibodies to human renin. Antibodies in the hybridoma culture medium were screened by binding to pure iodinated renin or insolubilized renin in a solid phase assay. The concentration of purified antibodies that provided a 50% binding to iodinated renin varied from 1 X 10(-10) to 1 X 10(-7) M. Two monoclonal antibodies were found to be potent inhibitors of renin enzymatic activity in vitro, behaving as noncompetitive inhibitors (Ki, 1 to 4 X 10(-10) M). They were specific for primate renin. Three monoclonal antibodies provided suitable immunoadsorbants for renin purification. One of these immunoadsorbants was used for large-scale purification of the renal enzyme, resulting in an 825-fold renin enrichment in a single step. Two antibodies were able to distinguish between active and inactive renin and enabled concomitant separation and purification of the two enzyme forms in various biological fluids. Monoclonal antibodies also stained human and monkey renal renin when indirect immunofluorescence and peroxidase-antiperoxidase techniques were used. A highly sensitive radioimmunometric assay of renin was constructed with two monoclonal antibodies. The sensitivity of this improved assay should permit the detection of renin in normal human plasma. Monoclonal antibodies have been shown to be superior to polyclonal antibodies in the following areas: the separation of active from inactive renin, the purification of renin from biological fluids, and the setting up of a direct assay of plasma renin.

Amniotic Fluid↗
PubMed1975

Correlation between juxtaglomerular index, kidney renin content and plasma renin concentration in the rat.

The correlation between juxtaglomerular index, kidney renin content, and plasma renin concentration has been investigated in rats. The results indicate that renin exists in two forms. When determining the renin content of the kidney, the renin actually present in the modified smooth muscle cells of the juxtaglomerular apparatus is measured; this is called bound renin. The amount of bound renin is derived from the total of granular and subgranular renin in the modified smooth muscle cells. Since JGI and KRCont show a significant positive correlation in untreated adult rats, it is assumed that in such animals the ratio of granular and subgranular renin is constant. Since no correlation could be demonstrated between kidney renin content and PRC in untreated adult rats, and JGI and KRCont did not change parallel with the increase of PRC in numerous experimental conditions, it is assumed that part of the renin synthetized in the JG cells is secreted directly, without passing the process of condensation into membrane bound granules. This mobile renin does not significantly affect the renin content and the JGI of the kidney. Under physiological circumstances, most of the produced renin seems to mature to granules in the modified smooth muscle cells before being secreted. When renin production and release increased, maturation to granules may be inhibited, a significant part of the produced renin released by direct secretion, and the subgranular, immature renin may also be secreted.

Adrenalectomy↗
PubMed1982

Effects of stimulation of renin release on trypsin-activable renin in rat plasma.

Little information is available concerning inactive renin in rat plasma. A renin assay method has now been developed for measurement of active and inactive renin in approximately 0.1 ml rat plasma. Trypsin treatment of plasma (5.0 mg trypsin/ml plasma for 5 min at 0 degrees C) to maximally increase the rate of angiotensin I generation did not alter the Km or pH optimum of the renin reaction. Utilizing trypsin, 79 +/- 6% of the total renin (active + inactive) in normal rat plasma is in the inactive form. In vivo stimulation of renin by restraint stress induces a reciprocal change in active and inactive plasma plasma renin, and exposure of animals to ether elevates active and total renin, whereas inactive renin shows a small but nonstatistical decline. Although a parallel disappearance of active and inactive renin is observed after bilateral nephrectomy of the pentobarbital-anesthetized animal, complete occlusion of the renal arteries and veins after ether-induced renin stimulation results in a significant increase of inactive renin. This suggests that possibility of formation of inactive renin from the active enzyme in high renin states. These studies indicate that the balance of active and trypsin-activable renins in rat plasma may be dependent or not only the method but also the degree of in vivo renin stimulation.

Angiotensin I↗
PubMed1994

Renin and renin mRNA in proximal tubules of the rat kidney.

The present study was undertaken to assess the presence of renin enzymatic activity and renin mRNA in proximal tubules of rat kidneys, and to determine the effect of converting enzyme inhibition (CEI) on proximal tubule renin gene expression. Proximal convoluted tubules (PCT), proximal straight tubules (PST), outer medullary collecting ducts (OMCD), and glomeruli (Gloms) were isolated by microdissection. Renin activity was measured in sonicated segments by radioimmunoassay. Renin mRNA levels were assessed using a quantitative PCR. Renin activity in PCT averaged 51 +/- 15 microGU/mm compared to 405 +/- 120 microGU/glomerulus. No measurable renin activity was found in PST and OMCD. Renin activity in both glomeruli and tubules had the same pH optimum, between 7.0 and 7.5. Renin mRNA was consistently detectable in cDNA prepared from PCT and PST, although its abundance per mm tubule was about 1/500th that found in one glomerulus. Renin mRNA was not detectable in OMCD. Tubular renin PCR product identity was confirmed by restriction digestion. CEI administration increased glomerular renin activity and renin mRNA, but not proximal tubular renin. The absence of a stimulatory effect of CEI on proximal tubule renin gene expression suggests the operation of different intracellular signals in control of renin synthesis in the proximal tubule than in the vascular compartment.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Characterization of purified rabbit uterine renin: influence of pregnancy on uterine inactive renin.

Using specific antibody raised against renal renin, we have documented that the majority of the uterine renin-like activity in gravid and nongravid uteri is immunoreactive renin. To characterize its physiochemical properties, we obtained highly purified uterine renin by two affinity chromatographic steps, pepstatin and antirenin. Uterine renin has a pH optimum of 6, an apparent mol wt of 38K, and a Km of 1.7 microM for homologous substrate. These properties are identical to those of renal renin and are not influenced by the pregnant state. In the basal state, an inactive form of the uterine enzyme constitute 55 +/- 10% of the total uterine renin. During pregnancy, active renin increased 40-fold as inactive renin fell to 4 +/- 3% of the total renin concentration. The renal renin concentration fell as plasma renin increased during pregnancy. These data suggest that the increased uterine renin concentrations during pregnancy are probably due to increased local production and conversion of renin precursor to the active enzyme. This stimulation of the uterine renin level appears to be independent of renal renin.

Animals↗
PubMed1986

Is renin secreted by exocytotic mechanism through mature renin granules from juxtaglomerular cells?

Mature renin granules were isolated by the combination of discontinuous and continuous Percoll density gradient centrifugation. Stored renin in the renin granules was found to consist of isoelectrically seven different forms. The seven different isoelectric points (pIs) were 5.6, 5.35, 5.2, 5.0, 4.8, 4.6 and 4.4. Approximately 70% of the stored renin as the total enzymatic activities from all isoelectric peaks was found in a peak which pI corresponded to be 5.35. Renin secreted from isolated glomeruli was also focused into seven peaks possessing identical values. However, the distribution pattern of renin peaks was quite different from that of stored renin. In the secreted renin, peaks of 5.35 (pI) and 5.2 (pI) showed high renin activity and each had approximately 30% of released renin as the total recovered. These results indicate multiple forms of renin are stored and secreted by rat kidney. As the distribution pattern of enzymatic activities in renin peaks between stored renin and secreted renin are different, it is probable that renin may not secreted through mature renin granules by exocytotic mechanism.

Animals↗
PubMed1989

Effects of aging on human plasma renin: simultaneous multiple assays of enzyme activity and immunoactivity of plasma renin.

The effects of aging on plasma renin in normotensive volunteers were evaluated by conventional indirect RIA of angiotensin I and a newly developed direct RIA. Plasma renin activity and the plasma concentration of active renin measured by radiometric assay with monoclonal antibody were significantly lower in 14 subjects over 60 years than in 15 subjects under 60 years (plasma renin activity: 0.5 +/- 0.1 vs 1.7 +/- 0.4 nmol.1-1.h-1, P less than 0.01; plasma active renin: 0.50 +/- 0.05 vs 0.87 +/- 0.13 pmol/l, P less than 0.01, means +/- SEM), whereas neither the total renin activity nor the total plasma renin concentration measured by the newly developed immunometric assay were different in the two groups. In another study, the plasma renin concentration, total renin concentration and immunoreactive total renin concentration measured by direct RIA with polyclonal antibody were determined in 17 young (less than 60 years) and 12 elderly (greater than or equal to 60 years) subjects. Plasma renin concentration was significantly lower in the elderly subjects (1.7 +/- 0.2 nmol.l-1.h-1) than in young subjects (3.2 +/- 0.7 nmol.l-1.h-3, P less than 0.05), but the total renin concentration and immunoreactive total renin concentrations in the two groups were not significantly different. These results indicate that the total renin content of the plasma does not change, whereas the active renin content decreases with age in normal subjects, and suggest that activation of prorenin to active renin may be impaired in elderly subjects.

Adult↗
PubMed1993

Anti-renin T cells trigger normal B cells to produce anti-renin antibodies and normalize blood pressure in spontaneously hypertensive rats.

Spontaneously hypertensive (SH) rats immunized with mouse renin produce anti-renin antibodies, responsible for down-modulation of blood pressure, associated with an infiltration of kidneys by mononuclear cells. In this work, anti-renin T cells from SH rats immunized with renin have been stimulated in vitro, and we have studied in vitro and in vivo their effect on anti-renin antibody production by normal syngeneic B cells. We show that, in vitro, renin-activated T cells induce a renin-specific antibody response without addition of exogenous renin. Anti-renin T cells injected into naive SH rats trigger normal B cells to secrete high amounts of monospecific anti-renin IgG antibodies as early as day 5. These antibodies interfere with the homeostasis of the renin-angiotensin system leading to the normalization of blood pressure without any nephritis. These results show that anti-renin B cells are either not tolerant per se or in a reversible state of anergy. Our results also suggest that anti-renin B cells constitutively express renin-derived peptides in such a way that they may be stimulated by activated anti-renin T cells; these cells express IL-4 mRNA indicating that IL-4 could play a role in the differentiation of B cells.

Animals↗
PubMed1999

Effect of renal perfusion pressure on renal function, renin release and renin and angiotensinogen gene expression in rats.

1. A study was undertaken to examine the influence of acute renal perfusion pressure (RPP) reduction on renin release, renal renin and angiotensinogen gene expression and the role played by angiotensin II in these responses. 2. In chloralose-urethane anaesthetised rats, reduction of RPP to 60 mmHg for 3 h in vehicle or losartan-treated (5 days at 10 mg kg-1 bis in die (b.i.d.)) rats decreased renal blood flow by 46 and 29 % (both P < 0.001), respectively, glomerular filtration rate by 45 and 57 % (both P < 0.001), respectively, and sodium excretion by 96 and 98 % (both P < 0.01). 3. Chloralose-urethane anaesthesia and surgery caused a rise in plasma renin activity but was associated with a suppression of renal renin (50 %, P < 0.01) and angiotensinogen (40 %, P < 0.05) gene expression. Following reduction of RPP to 60 mmHg for 3 h, plasma renin activity was increased more than 7-fold (P < 0.001) and renal renin gene expression about 2-fold (P < 0.05). 4. Chronic (5 days) blockade of angiotensin II receptors with losartan elevated plasma renin activity some 29-fold (P < 0.001) and caused a marked increase (30-fold, P < 0.05) in renal renin gene expression, compatible with angiotensin II exerting a negative feedback control on renin release and gene expression. Reduction of RPP to 60 mmHg for 3 h in these animals had little effect on renal renin gene expression. 5. From these findings it can be concluded that (a) chloralose-urethane anaesthesia and surgery had a stimulatory effect on renin release but suppressed basal levels of renal renin and angiotensinogen gene expression; (b) acute reduction of RPP for 3 h could stimulate renin gene expression in the renin producing cells; and (c) the negative feedback control of angiotensin II on renin release and synthesis which was evident following chronic losartan treatment was not apparent during short-term reduction of RPP.

Angiotensin II↗
PubMed1978

A comparison of cold and acid activation of big renin and of inactive renin in normal plasma.

Normal human plasma contains "inactive renin," whose ability to generate angiotensin I increases after exposure to pH 3.3. Big renin is a partially inactive enzyme of larger molecular weight, which is also activated at pH 3.3, and is found of pregnant women, and in amniotic fluid, but not in normal plasma. We have compared the effects of acid exposure and storage at 4 and -4 C on normal plasma and plasma containing big renin. The concentration of inactive renin in normal plasma was approximately equal to that of normal active renin, and its activity increased slowly on prolonged standing at -4 but not 4 C. In contrast, the activity of big renin increased by 50% as early as 1-3 days at 4 C and increased even more quickly at -4 C. Acid treatment of plasma containing big renin caused 4-10 times greater increase in active renin than similar treatment of normal plasma. During gel filtration, both cold-activated and previously acidified big renin coeluted with unactivated big renin. These data indicate that big renin is highly susceptible to cold or acid activation and that such activation of big renin does not result in a detectable decrease in its molecular weight of 60,000 daltons. Furthermore, acid and cold seem to activate the same pool of inactive renin in normal plasma. Although both normal and big renin are stable for long periods below -20 C, a serious overestimate of plasma renin activity can occur if plasma is stored just above its freezing point before assay.

Amniotic Fluid↗
PubMed1983

Plasma inactive renin in diabetic patients with neuropathy: a role for the sympathetic nervous system in the conversion in vivo of inactive renin.

Plasma levels of active and trypsin-activatable inactive renin and catecholamines were measured in 6 diabetic patients with neuropathy (group 1), 8 diabetic patients without neuropathy (group 2) and 8 age-matched normal subjects. The effect of insulin administration on plasma active and inactive renin and plasma catecholamine levels in diabetic patients was also investigated. The levels of inactive renin were calculated as the difference between the levels of total renin after trypsin activation and those of active renin. The levels of plasma catecholamines were determined by the trihydroxyindole method. The levels of active renin were significantly lower and inactive renin was increased slightly in group 1 when compared with controls. Group 1 showed a significant reduction in plasma norepinephrine levels. Group 2 showed slightly reduced active renin, normal inactive renin and normal norepinephrine values. There was no significant difference in the levels of epinephrine between the 3 groups. After insulin injection, active renin levels were increased in groups 1 and 2. The mean increment in active renin levels was less in group 1 than in group 2. Inactive renin levels were slightly decreased in both groups. Significant increases in epinephrine and norepinephrine levels were observed following insulin administration. The mean increment in norepinephrine levels was less in group 1 than in group 2. There was a positive correlation between the mean increment in active renin and in norepinephrine levels in diabetic patients. These results suggest that the impaired conversion of inactive renin into an active form is responsible in part for the low levels of active renin in diabetics with neuropathy.

Diabetes Mellitus↗
PubMed1987

Comparative measurements of immunoreactive renin, plasma renin activity and angiotensin II in human plasma.

In human plasma samples we compared the values of renin activity, determined with a conventional enzymatic assay, with those of immunoreactive renin, determined with a new, direct immunoradiometric assay which employs highly specific monoclonal antibodies, and with those of angiotensin II; the comparative measurements of renin were carried out also in trypsin activated samples of nephric and anephric subjects. We found that, overall, there was a close relationship between renin activity and immunoreactive renin; however, this relationship was absent when the statistical analysis was restricted to plasmas with low or very low renin. We also found that, within a rather wide range of values, angiotensin II was more closely correlated with immunoreactive renin than with renin activity. Trypsin activation increased to a similar extent immunoreactive renin and renin activity in plasma of nephric and anephric subjects and, overall, the values of total renin obtained with the two assays were significantly correlated. The results of these comparative determinations indicate that, in general, the measurement of immunoreactive renin represents a valid alternative to that of renin activity and a reliable index of the activity of the renin-angiotensin system. In addition, studies with trypsin activation suggest that even in the anephric state human plasma contains an inactive enzyme convertible into an active form which has immunological properties similar to those of active renin.

Angiotensin II↗
PubMed2004

Lectin chromatography of extrarenal renin protein in human plasma and tissues: potential endocrine function via the renin receptor.

Secretion of prorenin from extrarenal tissues comprises approximately half of the renin protein in plasma; its origin is unknown. The discovery of a prorenin/renin receptor that activates vascular tissue kinases raises interest in this otherwise inactive component. We have studied its glycosylation as this may distinguish it from renal renin. The binding of renin protein (active and prorenin) in human plasma and tissues to concanavalin (Con A) and wheat germ lectins was deployed. Immunoradiometric and enzyme kinetic assays were applied to column fractions. Mannosylated renin protein binds to Con A and has been shown to be taken up by human vascular and hepatic cells on mannose-6-phosphate receptors, possibly as a clearance mechanism. But the other binding sites of prorenin/renin that elicit a cellular phosphorylation response are apparently independent of glycosylation. The tissues examined (kidney, adrenal, ovary) each contain high proportions of Con A binding renin, but the plasma of normal resting males and females contain mainly non-binding renin, the proportion increasing as renal renin secretion decreases. The extreme of this relationship is seen in anephric patients and in some normal women on oral contraceptives with suppressed renal renin, in whom plasma renin is entirely non-binding to Con A. Conversely, when renal renin secretion was stimulated, the increased plasma active renin bound to Con A. However, extrarenal tissues containing exclusively Con A non-binding renin protein, and hence potential sources of anephric plasma renin protein, were not identified, but are unlikely to include adrenal or female reproductive tract. The findings are consistent with the view that normal human plasma contains a considerable amount of amannosylated prorenin of extrarenal origin that escapes hepatic clearance and has a longer half-life than renal renin. This plasma renin form would be expected to be activated in association with the recently described renin/prorenin aspartyl protease receptor and to participate in local pathophysiological processes.

Adrenal Glands↗
PubMed1990

Isolation and characterization of renin-expressing cell lines from transgenic mice containing a renin-promoter viral oncogene fusion construct.

We constructed transgenic mice containing a renin-promoter SV40 T antigen fusion transgene with the intention of inducing neoplasia in renin-expressing cells and isolating renin-expressing cell lines in vitro. We examined six kidney tumors from mice representing three different transgenic lines and found they expressed their endogenous renin gene. Initially, five nonclonal kidney tumor-derived cell lines were established which expressed their endogenous renin gene in addition to the transgene. They retained active renin intracellularly and constitutively secreted an inactive form of renin (prorenin). One of these cell lines was cloned to homogeneity. This line maintained high level expression of renin mRNA throughout 3 months of continuous culture. Although the cells contained an equal proportion of active and inactive renin, the species constitutively secreted into the media was predominantly (95%) prorenin. However, active renin secretion was stimulated 2.3- and 4.6-fold by treatment with 8-bromo-cAMP after 4 and 15 h, respectively. In addition, the presence of multiple secretory granules was confirmed by ultrastructural analysis. These cells, which express renin mRNA and can regulate secretion of active renin, should provide an excellent tool for studying renin gene regulation and secretion. Furthermore, these mice should provide a useful source for the establishment of renin-expressing cell lines from a variety of renin-expressing tissues.

Animals↗
PubMed1996

Active renin and renin glycoform dynamics in the carotid artery.

Active renin and five major active renin glycoforms were measured in plasma and the carotid wall of anesthetized rabbits before and after 1.5- and 24-h bilateral nephrectomy (BNX). Before BNX, there was no difference in renin glycoform proportions between plasma and the carotid wall. Plasma renin concentration (PRC) fell by 67% after 1.5-h BNX due to preferential clearance of renin glycoforms I+II, but no significant change in renin concentration was seen in the carotid artery (or aorta). Twenty-four hours after BNX, PRC and carotid wall renin concentrations were reduced by 99.7 and 97.7%, respectively, while the proportion of renin glycoforms I+II in the carotid wall was significantly elevated. These data are consistent with the view that vascular renin is derived from plasma renin of renal origin. After BNX, renin disappearance from the carotid (and aortic wall) is slower than renin decay from plasma, and the less negatively charged active renin glycoforms I+II exit the carotid wall much more slowly than the more negatively charged glycoforms. After 24-h BNX, renin glycoforms I+II were still effluxing from the vascular wall and represented the only glycoforms present in the carotid wall.

Animals↗
PubMed1987

Inactive renin in peritoneal fluid of the cat: responses to acute stimuli which alter plasma renin.

Active and inactive renin in plasma and peritoneal dialysate were studied in pentobarbitone anesthetized cats during 8 hours of peritoneal dialysis. In control cats, despite a significant rise in plasma active renin from 1.3 +/- 0.22 to 4.4 +/- 0.76 pmoles AI/ml/hr over 8 hours, plasma inactive renin was unchanged. Four-fold rises in plasma active renin after hemorrhage (15 ml/kg) and captopril (1 mg/Kg I.V.) were unaccompanied by significant change in inactive renin. Bilateral nephrectomy resulted in undetectable plasma active renin after 3 hours but plasma inactive renin was 25-30% of initial levels 6 hours post-nephrectomy. In peritoneal dialysate, active renin remained low in control cats but there was a ten-fold rise of inactive renin from 0.06 +/- 0.02 to 0.60 +/- 0.07 pmoles AI/ml/hr. After hemorrhage there was a slight rise of active renin after 3 and 4 hours. Inactive renin was lower than control 6 hours after nephrectomy and captopril, but higher than control 1 and 2 hours after hemorrhage. Dialysate inactive renin accumulation slopes were not different among treatments. Acute changes in plasma active renin have little effect on peritoneal dialysate renin.

Animals↗
PubMed1999

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors.

The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(-1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.

Administration, Oral↗