Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of the low renin state in DM is not clear. To assess the role of certain growth and regulatory factors in this process, we studied the effects of insulin, IGF-I, and IGF-II on the renin-angiotensin system in normal and 8-wk STZ-induced diabetic rats. Renin secretion was studied both in static incubations and by perifusion of rat renal cortical slices. In diabetic rats, both plasma renin activity (0.65 +/- 1.6 vs. 4.0 +/- 1.2 ng ANG I.ml-1.h-1) and tissue renin concentrations (27 +/- 5 vs. 51 +/- 8 ng ANG I.mg tissue-1.h-1) were reduced. Insulin (0.1-1.0 mu/ml) and IGF-I (10(-9) to 4 x 10(-9) M) stimulated renin secretion in normal tissue (control, 95 +/- 3%; insulin [0.5 mu/ml], 134 +/- 7%; IGF-I [4 x 10(-9) M], 149 +/- 7%). IGF-I stimulated renin secretion in perifusions as early as 30 min, whereas IGF-II had no effect. However, in diabetic renal tissue, neither insulin (0.1-1.0 mu/ml) nor IGF-I (10(-9) to 4 x 10(-9) M) had an effect on renin. This lack of effect was overcome by adding up to 100-fold higher concentrations of these growth factors. ANG II (10(-10) M-10(-8) M) had an exaggerated inhibitory effect on renin secretion in diabetic tissue. This study suggests that the low renin state in DM may be explained by the enhanced inhibitory effect of ANG II and the resistance to the secretogogue actions of insulin and IGF-I.
 ...
PMID:Altered regulation of renin secretion by insulinlike growth factors and angiotensin II in diabetic rats. 138 18

The relationship between the renin-angiotensin system (RAS) and prostacyclin (PGI2) biosynthesis was studied in experimental diabetic rats. The group with diabetes induced by streptozotocin (STZ, 3.3 mmol/kg i.v.) showed prolonged hypertension, and plasma renin activity decreased markedly from 8.4 +/- 0.7 to 2.4 +/- 0.3 and 1.2 +/- 0.3 ng angiotensin I/ml per h at 2 and 8 weeks after STZ treatment. Plasma PGI2, determined as 6-keto-PGF1 alpha, decreased significantly at 8 weeks, with the values for the STZ-treated and control groups being 1490 +/- 99 and 2210 +/- 90 pg/ml, respectively. Significant suppression of renin release from renal cortical slices was observed at 8 weeks in the diabetic group, although no significant change was found in the renal renin content when compared with that of the controls. The release of PGI2 from the renal medullary slices of the diabetic group was suppressed at 2 and 8 weeks, with the suppression in aorta and renal cortical slices being apparent only at 8 weeks. These results indicate that suppression of the RAS may be related to PGI2 biosynthesis in diabetes mellitus.
 ...
PMID:Renin-angiotensin system and prostacyclin biosynthesis in streptozotocin diabetic rats. 636 Jun 95

We have previously reported that chronic hypertension develops consistently in Wistar rats with a 25% reduction in renal mass (RRM) following the induction of insulin dependent diabetes mellitus (IDDM) with streptozotocin (STZ, 65 mg/kg body weight, intravenously). In this study, we examined the role of the endogenous digitalis-like substance in the development of hypertension. Four groups of rats were studied: 1) 25% RRM rats with STZ-induced IDDM (25-DM), 2) normal rats with STZ-induced IDDM (2K-DM), 3) 25% RRM rats with vehicle treatment (25-V), and 4) normal rats with vehicle treatment (2K-V). In 25-DM rats, blood pressure progressively increased during the 3 weeks after STZ treatment and was associated with microalbuminuria, low plasma renin activity, and extracellular volume expansion. In contrast, the 2K-DM, 25-V, and 2K-V rats remained normotensive. Furthermore, the plasma and urine levels of digoxin-like immunoreactive factor (DIF), determined by digoxin radioimmunoassay (Baxter), were significantly higher in hypertensive 25-DM rats than in their controls. The same was the case for plasma digitalis-like substance (DLS), determined by exposing canine Na+,K(+)-ATPase to plasma fractions and observing the percent inhibition. Increased DIF and DLS in hypertensive 25-DM rats was associated with a significant decrease in Na+,K(+)-ATPase activity of microsomes prepared from the left and right ventricles, when compared with microsomes from normotensive 2K-DM animals. Microsomal 5'-nucleotidase, a plasma membrane marker, was unchanged. The DIF and DLS correlated significantly with each other and with myocardial Na+,K(+)-ATPase activity and mean blood pressure. These results suggest that increased endogenous digitalis-like substance, which inhibits cardiovascular muscle cell Na(+)-K(+)-pump activity, may be involved in the mechanism of hypertension associated with IDDM in 25% RRM rats.
 ...
PMID:Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes in reduced renal mass rats. 839 Feb 68

The effect of the angiotensin-converting enzyme inhibitor, perindopril, on functional and structural parameters of diabetic nephropathy has been compared with triple therapy (hydralazine, reserpine, and hydrochlorothiazide) in normotensive, STZ-induced diabetic Sprague-Dawley rats. Animal groups included control rats, diabetic rats treated with perindopril, diabetic rats receiving triple therapy, and untreated diabetic rats. Treatment was continued for 32 wk. Blood pressure reduction and severity of diabetes, as assessed by body weight and glycemic control were similar with both drug regimens. A similar rise in plasma renin activity occurred in the two groups receiving antihypertensive drugs, whereas the perindopril but not the triple therapy group had suppressed plasma angiotensin-converting enzyme activity. No significant difference was observed in renal function among the four groups. Diabetes was associated with a progressive increase in albuminuria, but this rise was ameliorated by both perindopril and triple therapy. No significant difference was noted in albuminuria between triple therapy and perindopril-treated diabetic rats. Diabetes was associated with glomerular basement membrane thickening, mesangial expansion, and glomerular volume. No glomerular ultrastructural parameter was affected by antihypertensive drugs. No specific benefit of angiotensin-converting enzyme inhibition over triple therapy could be detected in this normotensive model of diabetic nephropathy.
 ...
PMID:The effects of perindopril and triple therapy in a normotensive model of diabetic nephropathy. 845 12

1. Transient and sustained calcium-independent outward K(+) currents (I(t) and I(SS)) as well as action potentials were recorded in cardiac ventricular myocytes isolated from two models of diabetes mellitus. 2. Rats injected (I.V.) with streptozotocin (STZ, 100 mg kg(-1)) 6-10 days before cell isolation developed insulin-dependent (type 1) diabetes. I(t) and I(SS) were attenuated and the action potential prolonged. Incubation of myocytes (6-9 h) with the angiotensin II (ATII) receptor blockers saralasin or valsartan (1 microM) significantly augmented these currents. Inclusion of valsartan (1 g l(-1)) in the drinking water for 5-10 days prior to and following STZ injection partially prevented current attenuation. 3. Incubation of myocytes from STZ-treated rats (6-9 h) with 1 microM quinapril, an angiotensin-converting enzyme (ACE) inhibitor, significantly augmented I(t) and I(SS) and shortened the ventricular action potential. I(t) augmentation was not due to changes in steady-state inactivation or in recovery from inactivation. No acute effects of quinapril were observed. 4. The effects of quinapril and valsartan were abolished by 2 microM cycloheximide. 5. Myocytes were isolated from the db/db mouse, a leptin receptor mutant that develops symptoms of non-insulin-dependent (type 2) diabetes. K+ currents in these cells were also attenuated, and the action potentials prolonged. Incubation of these cells (> 6 h) with valsartan (1 microM) significantly enhanced the transient and sustained outward currents. 6. These results confirm recent suggestions that cardiac myocytes contain a renin-angiotensin system, which is activated in diabetes. It is proposed that chronic release of ATII leads to changes in ionic currents and action potentials, which can be reversed by blocking the formation or action of ATII. This may underlie the proven benefits of ATII receptor blockade or ACE inhibition in diabetes, by providing protection against cardiac arrhythmias.
 ...
PMID:Inhibition of the formation or action of angiotensin II reverses attenuated K+ currents in type 1 and type 2 diabetes. 1171 63

Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibitors have been shown to inhibit atherosclerosis in apoE-deficient mice and in several other animal models but failed in low-density lipoprotein (LDL) receptor-deficient mice despite effective inhibition of the renin-angiotensin-aldosterone system. The aim of the present study was to examine the effect of omapatrilat on atherogenesis in diabetic and nondiabetic LDL receptor-deficient mice. LDL receptor-deficient male mice were randomly divided into 4 groups (n = 11 each). Diabetes was induced in 2 groups by low-dose STZ, the other 2 groups served as nondiabetic controls. Omapatrilat (70 mg/kg/day) was administered to one of the diabetic and to one of the nondiabetic groups. The diabetic and the nondiabetic mice were sacrificed after 3 and 5 weeks, respectively. The aortae were examined and the atherosclerotic plaque area was measured. The atherosclerotic plaque area was significantly smaller in the omapatrilat-treated mice, both diabetic and nondiabetic, as compared to nontreated controls. The mean plaque area of omapatrilat-treated nondiabetic mice was 9357 +/- 7293 microm2, versus 71977 +/- 34610 microm2 in the nontreated mice (P = .002). In the diabetic animals, the plaque area was 8887 +/- 5386 microm2 and 23220 +/- 10400 microm2, respectively for treated and nontreated mice (P = .001). Plasma lipids were increased by omapatrilat: Mean plasma cholesterol in treated mice, diabetic and nondiabetic combined, was 39.31 +/- 6.00 mmol/L, versus 33.12 +/- 7.64 mmol/L in the nontreated animals (P = .008). The corresponding combined mean values of triglycerides were 4.83 +/- 1.93 versus 3.00 +/- 1.26 mmol/L (P = .02). Omapatrilat treatment did not affect weight or plasma glucose levels. Treatment with omapatrilat inhibits atherogenesis in diabetic as well as nondiabetic LDL receptor-deficient mice despite an increase in plasma lipids, suggesting a direct effect on the arterial wall.
 ...
PMID:Omapatrilat, an angiotensin-converting enzyme and neutral endopeptidase inhibitor, attenuates early atherosclerosis in diabetic and in nondiabetic low-density lipoprotein receptor-deficient mice. 1274 71

Meprin (MEP) A is a metalloendopeptidase that is present in the renal proximal tubule brush-border membrane (BBM) and that colocalizes with angiotensin-converting enzyme (ACE). The MEP beta-chain gene locus on chromosome 18 has been linked to a heightened risk of diabetic nephropathy (DN) in patients with type 2 diabetes. This study evaluated 1) whether MEP-alpha and MEP-beta gene and protein expression are altered in db/db mice before the onset of DN and 2) the role of MEP-alpha in the pathogenesis of DN and the impact of the renin-angiotensin system on this interaction in two experimental models of diabetes. MEP-alpha and MEP-beta gene and protein expression were evaluated in db/db mice, 13-14 wk of age, compared with lean C57BLKS/J littermate animals. A treatment study was then performed in which db/db mice and controls were assigned to one of three groups: control (C) water, no therapy; ACE inhibitor therapy, enalapril (EN)-treated water, 50 mg/l; ANG II receptor type 1 blocker (ARB) therapy, losartan (LOS)-treated water, 500 mg/l. Treatment was started at 8 wk of age and continued for 52 wk. Male Sprague-Dawley rats with diabetes for 52 wk following a single dose of streptozocin (STZ; 60 mg/kg) were also studied. At 13.5 wk of age, MEP-alpha and MEP-beta kidney mRNA abundance and protein expression were significantly lower in db/db mice compared with lean controls, with greater changes in MEP-beta (P < 0.05). In the treatment study, EN ameliorated and LOS exacerbated DN in db/db mice. BBM MEP A enzymatic activity and MEP-alpha protein content were lower in db/db mice vs. control nonobese mice at 52 wk (P < 0.02). EN-treated db/db mice showed increased MEP A activity, MEP-alpha content in BBM, decreased urinary MEP-alpha excretion, and enhanced BBM staining for MEP-alpha protein vs. C and LOS-treated db/db mice. In nonobese mice, EN and LOS treatment had no effect on MEP-alpha expression. In rats with STZ-induced diabetes for 52 wk, urinary MEP-alpha excretion was increased and MEP A activity and MEP-alpha protein content per milligram of BBM protein were decreased compared with age-matched control animals (P < 0.05). These results indicate that db/db mice manifest decreased MEP-alpha and MEP-beta gene and protein expression, before the development of overt kidney disease. Moreover, in db/db mice with DN and rats with STZ-diabetes, there was an inverse relationship between renal MEP-alpha content and the severity of the renal injury. Treatment with an ACE inhibitor was more effective than ARB in ameliorating DN in db/db mice, a change that correlated with alterations in urinary excretion and BBM content of MEP-alpha. MEP-alpha may play a role in the pathogenesis of DN and the benefits of ACE inhibitor therapy on the progression of diabetic kidney disease may be related, in part, to its impact on renal MEP-alpha expression.
 ...
PMID:Meprin-alpha in chronic diabetic nephropathy: interaction with the renin-angiotensin axis. 1594 51

Danggui buxue tang (DBT), a preparation containing Angelica sinensis (danggui) and Astragalus membranaceus (huangqi) at a ratio of 1 : 5, is used widely in China for stimulating red blood cell production and enhancing cardiovascular function. The present study was undertaken to characterize the effects of this preparation on diabetic nephropathy using streptozotocin-diabetic rats as a model. Streptozotocin-dependent alterations in renal weight/body weight ratio, urinary albumin and beta (2)-microglobulin concentrations, urinary albumin excretion rate, and creatinine clearance were ameliorated after eight weeks of treatment with either DBT or the angiotensin-converting enzyme inhibitor, benazepril. DBT, but not benazepril, partially attenuated the increases in blood glucose, triglycerides and cholesterol in STZ-diabetic rats. Additionally, the increased expression of transforming growth factor-beta (1) mRNA in the renal cortex due to streptozotocin-induced diabetes was modestly attenuated by these treatments. However, eight weeks of treatment with DBT failed to modify the concentration of angiotensin II in plasma or kidney, indicating that the ability of the preparation to retard the progression of kidney disease was not attributable to inhibition of the renin-angiotensin system. We propose that DBT alleviates renal alterations in diabetes and slows the progression of diabetic nephropathy by suppressing transforming growth factor-beta (1) mRNA expression. The preparation may therefore be useful as an adjuvant therapy for controlling diabetes and its complications.
 ...
PMID:Suppression of transforming growth factor-beta1 gene expression by Danggui buxue tang, a traditional Chinese herbal preparation, in retarding the progress of renal damage in streptozotocin-induced diabetic rats. 1652 7

The renin-angiotensin system has been implicated in the etiology of the cardiovascular complications of diabetes. Our studies extend these findings to show a specific role for angiotensin AT1a receptors in mediating diabetes-induced hypertension. Male angiotensin AT1a knockout (AT1aKO) and wild-type (AT1aWT) mice with arterial telemetric catheters were injected with streptozotocin (STZ; 150 mg/kg ip). The STZ dose was selected on the basis of a dose-response experiment in C57/BL mice. Blood glucose, water intake, body weight, blood pressure (BP), and heart rate (HR) were measured over a 2-wk period. Estimates of BP and HR variance (BPV and HRV) and their low- and high-frequency domains were also determined. STZ induced similar levels of hyperglycemia and polydypsia in the groups. Mean arterial pressure (MAP) was increased from 100 +/- 6 to 124 +/- 6 mmHg in diabetic AT1aWT. MAP was unchanged in AT1aKO (80 +/- 4 vs. 85 +/- 5 mmHg, basal vs. STZ). Treatment with an ACE inhibitor, captopril, produced a greater reduction in MAP (-18%) in diabetic AT1aWT than in AT1aKO (-3.4%). BPV was lower in AT1aKO (19 +/- 0.5 vs. 9 +/- 2 mmHg(2), AT1aWT vs. AT1aKO). Diabetes reduced BPV but only in AT1aWT (19 +/- 0.5 vs. 8 +/- 1 mmHg(2), basal vs. STZ). There were no changes in HR in either group. In AT1aKO, STZ increased HRV and its high-frequency domain with no changes seen in AT1aWT. Results document that ANG AT1a receptors are critical in diabetes-induced hypertension and in cardiac autonomic responses.
 ...
PMID:Deficiency in angiotensin AT1a receptors prevents diabetes-induced hypertension. 1712 30

Many clinical trials have demonstrated that angiotensin converting enzyme inhibitors have protective effects on organ damage, suggesting the importance of inhibition of the renin-angiotensin system. In this study, we investigated the effects of a non-depressor dose of imidapril on organ damage induced by diabetes and hypertension. Diabetes was induced by an intravenous injection of streptozotocin (STZ, 40 mg/kg) in 15-week-old male spontaneously hypertensive rats (SHR). Imidapril (2 mg/kg/day) or vehicle was given orally for 28 days, and then the heart weight, left ventricle mass (LVM), urinary albumin excretion (UAE) and endothelial function were examined, as well as the urinary NOx level and local hepatocyte growth factor (HGF) expression. There were no significant differences between the treated groups in systolic blood pressure and plasma parameters. On the other hand, UAE was significantly suppressed in the imidapril-treated group (450+/-44 mg/day) compared to the vehicle-treated group (963+/-182 mg/day) (p<0.01). Moreover, endothelial function assessed by dilative reaction to acetylcholine as well as cardiac hypertrophy assessed by both heart/body weight ratio and LVM were significantly improved in the imidapril-treated group (p<0.05 and p<0.01, respectively). The urinary NOx concentration and local HGF expression in vessel walls were also significantly increased in the imidapril-treated group (p<0.01). A non-depressor dose of imidapril showed protective effects against organ damage in diabetic SHR, which may be partially due to the increase of HGF and NO.
 ...
PMID:Improvement of organ damage by a non-depressor dose of imidapril in diabetic spontaneously hypertensive rats. 1733 32


1 2 3 Next >>