benazepril and Diabetic-Nephropathies

When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction. altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and nonfatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications. (Am Fam Physician 2002;66:473.)

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Diabetic Nephropathies; Drug Costs; Enalapril; Fosinopril; Heart Failure; Humans; Hypertension; Indoles; Isoquinolines; Lisinopril; Meta-Analysis as Topic; Myocardial Infarction; Perindopril; Quinapril; Ramipril; Renin-Angiotensin System; Risk; Tetrahydroisoquinolines; United States

To evaluate whether angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) combination therapy is more nephroprotective than ACE inhibitor or ARB monotherapy in people with type 2 diabetes and overt nephropathy.. In this prospective, randomized, open, blind-endpoint phase III trial sponsored by the Italian Drug Agency, 103 consenting patients with type 2 diabetes, aged >40 years, with serum creatinine levels 159 to 309 μmol/L, spot morning urinary albumin-creatinine ratio > 1000 mg/g (or > 500 mg/g in those on ACE inhibitor or ARB therapy at inclusion) were stratified by centre and randomized to 4.5-year treatment with valsartan 320 mg/d (n = 36), benazepril 20 mg/d (n = 34) or halved doses of both medications (n = 33). The primary endpoint was end-stage renal disease (ESRD). Modified intention-to-treat analyses were performed.. Recruitment took place between June 2007 and February 2013 at 10 centres in Italy and one in Slovenia. A total of 77 participants completed the study and 26 were prematurely withdrawn. During a median (interquartile range) of 41 (18-54) months, 12 participants on benazepril (35.3%) and nine on combination therapy (27.3%) progressed to ESRD, versus five on valsartan (13.9%). Differences between benazepril (hazard ratio [HR] 3.59, 95% confidence interval [CI] 1.25-10.30; P = 0.018) or combination therapy (HR 3.28, 95% CI 1.07-10.0; P = 0.038) and valsartan were significant, even after adjustment for age, gender and baseline serum creatinine, systolic blood pressure and 24-hour proteinuria (HR 5.16, 95% CI 1.50-17.75, P = 0.009 and HR 4.75, 95% CI 1.01-22.39, P = 0.049, respectively). Adverse events were distributed similarly among the groups.. In people with type 2 diabetes with nephropathy, valsartan (320 mg/d) safely postponed ESRD more effectively than benazepril (20 mg/d) or than halved doses of both medications.

Topics: Adult; Aged; Benzazepines; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Female; Humans; Italy; Kidney Function Tests; Male; Middle Aged; Slovenia; Treatment Outcome; Valsartan

Brain-derived neurotrophic factor (BDNF) is associated with sympathetic activation. However, the effects of BDNF on diabetic nephropathy are unknown. The aim of this study was to assess the estimated glomerular filtration rates (eGFRs) and changes in serum BDNF levels in type 2 diabetic subjects treated with antihypertensive medications.. In this randomized, double-blind clinical trial, type 2 diabetic subjects with hypertension were assigned to either the benazepril/amlodipine or valsartan/hydrochlorothiazide treatment groups for a 16-week period. The post hoc analyses were based on increased or decreased serum BDNF levels.. Of the 153 enrolled subjects, the changes in eGFR were significantly and inversely correlated with those in BDNF in the 76 subjects treated with valsartan/hydrochlorothiazide (r = -0.264, P = 0.021) but not in the 77 subjects treated with benazepril/amlodipine (r = -0.025, P = 0.862). The 45 subjects with increased BDNF following valsartan/hydrochlorothiazide treatment exhibited a significantly reduced eGFR (-8.8 ± 14.9 mL/min/1.73 m(2); P < 0.001). Multivariate regression analysis revealed that increased serum BDNF represents an independent factor for reduced eGFR (95% confidence interval between -0.887 and -0.076, P = 0.020).. Increased serum BDNF is associated with reduced eGFR in type 2 diabetic subjects treated with valsartan/hydrochlorothiazide but not with amlodipine/benazepril.

Topics: Aged; Amlodipine; Antihypertensive Agents; Benzazepines; Brain-Derived Neurotrophic Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Male; Middle Aged; Valsartan

To observe the effect of combined therapy with Bailing Capsule (BC) and benazepril on the levels of urinary albumin excretion rate (UAER) and C-reactive protein (CRP) for exploring its protective effect on early diabetic nephropathy.. Sixty patients with early diabetic nephropathy were randomly assigned to the control group treated by benazepril alone, and the treated group treated by BC and benazepril, and the treatment lasted for 16 weeks. The changes of UAER and CRP levels were measured to estimate the protective effect of the combined therapy.. Levels of 24h urinary protein, UAER, CRP were (0.85 +/- 0.32) g/24 h, (83.34 +/- 38.27) microg/min, (2.67 +/- 1.72) mg/L before treatment in the control group, and (0.43 +/- 0.17) g/24 h, (71.22 +/- 31.12) microg/min, (1.05 +/- 0.78) mg/L after treatment and they were (0.87 +/- 0.31) g/24 h, (81.59 +/- 35.69) microg/min, (2.55 +/- 1.66) mg/L before treatment in treated group, and (0.25 +/- 0.29) g/24 h, (57.32 +/- 31.11) microg/min, (0.49 +/- 0.38) mg/L after treatment respectively, all of them decreased after treatment in both groups, showing significant differences as compared with those before treatment (P<0.05, P< 0.01), and the reduction in the treated group was more significant (P<0.01); meanwhile, levels of serum creatinine, fasting blood glucose and HbA1c had somewhat decrease, showing no statistical difference with those before treatment (P >0.05).. Combined use of BC and benazepril could significantly lower the UAER and CRP levels in patients with early diabetic nephropathy to alleviate the renal impairment, showing an effect better than that of using benazepril alone.

Topics: Adult; Aged; Albuminuria; Benzazepines; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Male; Middle Aged; Phytotherapy

To observe the clinical effect of combined treatment with safflor yellow powder injection and benazepril in treating patients with diabetic nephropathy (DN).. Seventy-six patients with DN were randomly assigned to the treatment group (39 cases) and the control group (37 cases). Conventional treatment for lowering blood glucose was given to both groups, but to the control group 10 mg benazepril was given orally once a day additionally, while to those in the treatment group the same dosage of benazepril po. and 150 mg/d of safflor yellow powder injection by adding in 250 mL 0.9% normal saline for intravenous dripping. The therapeutic course for them all was 15 days, and all patients received two courses with an interval of 5 days. Changes of clinical symptoms, urinary albumin excretion rate (UAER), blood and urinary levels of beta2 -microglobulin (beta2 -MG), urinary level of alpha1-microglobulin (alpha1 -MG), D-dimer (D-D) and plasma fibrinogen (FIB) were observed.. The total effective rate in the treatment group was higher than that in the control group (84.62% vs 59.45 %, P < 0.05). The total score of syndrome in the treatment group was lower than that in the control group (P < 0.05). Levels of UAER, 132-MG in serum and in urine, alpha1-MG in urine were decreased significantly after after 2 courses of treatment in both groups, showing significant difference as compared with before treatment (P < 0.05 or P <0.01), and the decrements were more significant in the treatment group than those in the control group (P <0.05); while decrease of FIB, D-D only happened in the treatment group (P <0.01), so the post-treatment data in the treatment group were significantly lower as compared with those in the control group (P <0.01).. Combined therapy with safflor yellow injection and benazepril is superior to benazepril alone in reducing urinary albumin, improving renal function and blood hyperviscosity manner for patients with DN, suggesting the combination of the two could play their respective superiorities and act in cooperation for retarding the progression of DN.

Topics: Adult; Albumins; Benzazepines; Blood Glucose; Diabetic Nephropathies; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Kidney Function Tests; Male; Middle Aged

Diabetic nephropathy management should include the use of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker with additional antihypertensive medications to reduce proteinuria and cardiovascular events. Some studies suggest that adding a nondihydropyridine rather than a dihydropyridine calcium channel blocker (CCB) may more effectively lower proteinuria. We hypothesized that a trandolapril/verapamil SR (T/V) fixed-dose combination (FDC) was superior to a benazepril/amlodipine (B/A) FDC for reducing albuminuria in 304 hypertensive diabetic nephropathy patients when treated for 36 weeks. No statistically significant differences were observed between groups in the primary end point; adjusted percentage change in urinary albumin/creatinine ratio (UACR), which increased (mean T/V, 29.29%; mean B/A, 8.49%; difference, 20.80%; P=.34); or in change in absolute UACR, which decreased (mean [g/g] T/V, -0.11; mean [g/g] B/A, -0.08; difference -0.03; P=.78). There were significant reductions in log UACR (mean change in T/V, -0.28; P<.01; mean change in B/A, -0.31; P<.001) and diastolic blood pressure in both groups and in systolic blood pressure in the B/A group. T/V was not superior to B/A for reducing UACR. Both ACEI/CCB FDCs may reduce albuminuria; in the case of T/V, this appears to be independent of systolic blood pressure reduction in patients who had previously been treated and had baseline blood pressure levels of 142/77 mm Hg.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Synergism; Drug Therapy, Combination; Female; Humans; Indoles; Male; Middle Aged; Prospective Studies; Proteinuria; Treatment Outcome; Verapamil

Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Treatment Outcome

To observe the protective effect on renal function of Chinese drugs combined with benazepril in patients with diabetic nephropathy (DN).. Adopting stratified randomized and controlled design, 108 patients with DN were assigned to two groups. Besides the same measures of diet regulation, exercise, education, hypoglycemic and symptomatic treatment applied, benazepril was administered to all patients, and Chinese drugs were given to patients in the treated group additionally. The treatment course was 3 months. The changes before and after treatment of symptoms and signs, 24-h urinary protein (24 hUpro), serum creatinine (SCr), serum creatinine clearance rate (CCr), blood urea nitrogen (BUN), plasma glucose (PG) and blood pressure (BP) were observed, and the time of dialysis therapy initiating was recorded.. SCr and 24 hUpro decreased and CCr increased in the treated group significantly (P < 0.01), and the improvement were superior to that in the control group (P < 0.05 or P < 0.01), the renal living time in the treated group was longer than that in the control group, but no significant different in BUN, PG and BP was found between the two groups (P > 0.05).. The treatment program of Chinese drugs combined with benazepril could obviously reduce the levels of SCr and 24 hUpro, increase CCr in patients with DN, and its effect in improving renal function is better than that of using benazepril alone.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Diabetic Nephropathies; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Male; Middle Aged; Phytotherapy; Treatment Outcome

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Circadian Rhythm; Diabetic Nephropathies; Humans; Renin-Angiotensin System; Risk Factors; Tetrazoles; Time Factors; Valine; Valsartan

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). The early stage of nephropathy is manifested by the presence of low levels of urinary albumin (microalbuminuria or urinary albumin excretion >or=30 and <299 mg/day). Albuminuria is a marker for development of nephropathy in type II diabetes and for increased cardiovascular morbidity and mortality. Recent studies have demonstrated the importance of antihypertensive agents that inhibit the renin-angiotensin-aldosterone (RAA) system to reduce the risk and slow down the progression of renal disease. A new clinical trial, GUARD (Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension), is designed to compare the change in urinary albumin to creatinine ratio after 1 year of initial treatment with either amlodipine besylate/benazepril HCl or benazepril HCl/hydrochlorothiazide. Other objectives include a comparison of the proportion of patients who progress to overt diabetic nephropathy and the safety of these two combination therapies in these high-risk patients.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renin-Angiotensin System; Research Design; Sodium Chloride Symporter Inhibitors

Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. This study tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor (ACE-I) and an Angiotensin-II receptor blocker (ARB) is superior to either drug alone in type I diabetic patients with diabetic nephropathy (DN). A randomized double-blind crossover trial was performed with 8-wk treatment with placebo, 20 mg of benazepril once daily, 80 mg of valsartan once daily, and the combination of 20 mg of benazepril and 80 mg of valsartan. Twenty type I diabetic patients with DN were included. At the end of each treatment period, albuminuria, 24-h BP, and GFR were measured. Eighteen patients completed the study. Placebo values were: albuminuria [mean (95% CI)], 701 (490 to 1002) mg/24 h; BP [mean (SEM)], 144 (4)/79 (2) mmHg, and GFR [mean (SEM)], 82 (7) ml/min per 1.73 m(2). Treatment with benazepril, valsartan, or dual blockade significantly reduced albuminuria and BP compared with placebo. Benazepril and valsartan were equally effective. Dual blockade induced an additional reduction in albuminuria of 43 % (29 to 54 %) compared with any type of monotherapy, and a reduction in systolic BP of 6 (0 to 13) mmHg and 7 (1 to 14) mmHg (versus benazepril and valsartan, respectively) and a reduction of 7 (4 to 10) mmHg diastolic compared with both monotherapies. GFR was reversibly reduced on dual blockade compared with monotherapy and placebo. All treatments were safe and well tolerated. In conclusion, dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN.

Topics: Adult; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Drug Synergism; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Tetrazoles; Valine; Valsartan

The coexistence of hypertension increases cardiovascular risks and the rate of deterioration of renal function for diabetic patients. For patients with left ventricular hypertrophy (LVH), the use of an angiotensin converting enzyme (ACE) inhibitor is known to be effective and well tolerated and to be protective against chronic renal insufficiency (CRI). However, serious adverse reactions to ACE inhibitors, such as the rapid deterioration of renal function, have been reported, making physicians hesitant to use these agents. To resolve this dilemma, we compared changes in renal function and left ventricular function and the safety and effectiveness of benazepril, an ACE inhibitor, in patients with diabetic nephropathy, with or without LVH. The age, sex, duration of diabetes, levels of blood pressure and blood glucose and rates of creatinine clearance (CrCl) were compared between 36 diabetic patients with LVH and 36 matched diabetic patients without LVH. The rates of CrCl in all patients were between 14 and 35 ml/min, and all patients received an ACE inhibitor before enrollment. The group comprised 43 men and 29 women, with a mean age of 56 +/- 4 years. These patients were divided into three groups, each of which was subdivided into a group with and a group without LVH. Group I (without LVH) or I-L (with LVH) received a half dose of benazepril (2.5 mg daily), Group II (without LVH) or II-L (with LVH) received a normal daily dose of 5 mg benazepril, and Group III (without LVH) or III-L (with LVH) discontinued the administration of the ACE inhibitor. The follow-up period was 1 year and, during the study, blood pressure was maintained at less than 140/90 mmHg. If the blood pressure control was not satisfactory, benidipine, a calcium antagonist, and/or furosemide, a loop diuretic, and/or guanabenz, a central acting antihypertensive agent, were administered. In the diabetic patients with LVH, the administration of a normal dose of benazepril inhibited the decline of renal function and cardiac function (CrCl: 24.2 +/- 1.5 to 22.0 +/- 2.5 ml/min; EF (ejection fraction): 56 +/- 3 to 54 +/- 6%) compared to the other two groups. In patients without LVH, a half dose of benazepril preserved renal function (23.4 +/- 2.6 to 22.0 +/- 3.1 ml/min; EF: 54 +/- 3 to 56 +/- 3%). Discontinuation of the administration of ACE inhibitor led to the further progression of renal dysfunction and decreases in EF in patients with or without LVH. Our results provide some indications for th

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Circadian Rhythm; Creatine; Diabetic Angiopathies; Diabetic Nephropathies; Dose-Response Relationship, Drug; Echocardiography; Female; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Male; Potassium; Proteinuria

Renal fibrosis is essential for the progression of diabetic nephropathy (DN). Macrophages accumulate in diabetic kidneys and are involved in epithelial-to-mesenchymal transition (EMT), a vital mechanism leading to renal fibrosis. Recently, high-mobility group nucleosome-binding protein 1(HMGN1) was documented in promoting the recruitment and activation of antigen-presenting cells. In this study, we first reported its roles in renal fibrosis and the underlying mechanism associated with macrophage filtration and EMT.. Twenty C57BL/6J mice were administered streptozotocin (STZ) to induce diabetes for 6 weeks and then divided into 4 groups: normal control group; DN group; benazepril-treated group, and insulin-treated group. Blood glucose, creatinine, and albumin in urine, hematoxylin and eosin, and Sirius red staining of kidney tissues were used to assess the renal pathology. ELISA, immunochemistry, and in situ hybridization were performed to determine the expression of HMGN1, CD68, F4/80, α-smooth muscle actin, and E-cadherin.. The renal expression levels of HMGN1, macrophage markers, and EMT makers were increased in DN group, and insulin treatment could reduce the overexpression of these indicators with a better effect than benazepril treatment. Both treatments could not obviously ameliorate urine albumin-to-creatinine ratio, collagen expression, and renal histological changes in STZ-induced diabetic mice. Correlation analysis indicated that there was a relationship among HMGN1, macrophage markers, EMT markers, and collagen expression in DN mice.. HMGN1 may promote macrophages accumulation and EMT, suggesting a potential therapeutic target for preventing renal fibrosis development in DN.

Topics: Animals; Benzazepines; Collagen; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Fibrosis; HMGN1 Protein; Insulin; Kidney; Macrophages; Mice; Mice, Inbred C57BL

This study was established to investigate the contribution of high mobility group nucleosome-binding protein 1 (HMGN1)/ Toll-like receptor 4 (TLR4) pathway in diabetic nephropathy (DN). And as an intervention of the potential mechanism above, the insulin growth factor 1 receptor (IGF-1R) inhibitor was examined for its therapeutic effect in the diabetic mice.. Male C57BL/6J mice were administered streptozotocin(STZ) to induce diabetes and thus divided into 5 groups: the untreated group (DN group), the benazepril-treated group (BEN-DN group), the insulin-treated group (INS-DN group) and the IGF-1R inhibitor-treated group (IGF-DN group). Immunohistochemistry and in situ hybrization were performed to detect the expression of HMGN1 and TLR4 in renal tissue. To evaluate the effect of IGF-1R inhibitor, levels of blood glucose and kidney/ body weight (KW/BW) were measured. And morphological changes and mesangial matrix expansion in kidneys were also detected.. Increased expression of HMGN1 and TLR4 in renal tissue of STZ-induced type1 diabetic mellitus (T1DM) mice models was observed. IGF-1R inhibitor attenuate the established nephropathy with reduced expression of TLR4 protein, as revealed by a decrease in mesangial index.. IGF-1R inhibitor might have therapeutic potential in DN through inhibition of HMGN1/TLR4 pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Diabetic Nephropathies; HMGN1 Protein; Male; Mice; Mice, Inbred C57BL; Receptor, IGF Type 1; Signal Transduction; Toll-Like Receptor 4

This study aimed to investigate the effects of benazepril hydrochloride (BH) on proteinuria and ANGPTL-4 expression in a diabetic nephropathy (DN) rat model.. A total of 72 Wistar male rats were randomly divided into three groups: normal control (NC), DN group and BH treatment (BH) groups. The DN model was induced by streptozotocin (STZ). Weight, glucose, proteinuria, biochemical indicators and the kidney weight index were examined at 8, 12 and 16 weeks. In addition, ANGPTL-4 protein and mRNA expressions were assessed by immunohistochemistry and qRT-PCR, respectively. Relationships between ANGPTL-4 and biochemical indicators were investigated using Spearman analysis.. Weight was significantly lower but glucose levels were significantly higher in both the DN and BH groups than in the NC group (P < 0.05). Compared with the DN group, proteinuria, urea, creatinine, triglycerides and total cholesterol levels were decreased, whereas the albumin level was increased after BH treatment (all P < 0.05). Furthermore, BH diminished kidney volume and ameliorated the pathological changes associated with DN. ANGPTL-4 expression was significantly decreased after BH treatment, and ANGPTL-4 expression was highly correlated with biochemical indicators of DN (P < 0.05).. Benazepril hydrochloride improves DN and decreases proteinuria by decreasing ANGPTL-4 expression.

Topics: Angiopoietin-Like Protein 4; Animals; Antihypertensive Agents; Benzazepines; Blood Glucose; Cholesterol; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Male; Organ Size; Proteinuria; Rats; Rats, Wistar; RNA, Messenger; Serum Albumin; Triglycerides; Up-Regulation; Urea

Recent studies in animal models have revealed that mycophenolate mofetil (MMF) has certain protective effects against experimental diabetic nephropathy. The present study therefore aimed to investigate the hypothesis that diabetic nephropathy may be ameliorated by mycophenolate mofetil and benazepril treatment alone or in combination, and identify the potential underlying mechanisms in a rat model. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin. Rats were subsequently treated with benazepril, MMF or a combination of the two drugs, and blood glucose, normalized kidney weight, urine protein and serum creatinine were determined. The pathological changes in renal tissue were also observed. In addition, indices of epithelial mesenchymal transition, including α‑smooth muscle actin (α‑SMA) and transforming growth factor (TGF)‑β1 expression, were examined. Normalized kidney weight, urine protein and serum creatinine levels were significantly improved in the diabetic rats treated with benazepril or mycophenolate mofetil, compared with those of rats in the untreated diabetic group. Pathological changes in the kidney were detected concurrently with increasing kidney weight and urinary albumin excretion, with a similar trend in variation among groups. In addition, the expression of epithelial mesenchymal transition indices, including α‑SMA and TGF‑β1, in the renal tubule interstitium were significantly decreased in the benazepril‑ and MMF‑treated groups compared with those of the diabetic group. As expected, the aforementioned indices were markedly lower in the benazepril and MMF combined treatment group than those in the single medication groups. These data suggested that MMF may have a protective role in diabetic nephropathy, and that the underlying mechanism may be partially dependent upon the suppression of the epithelial mesenchymal transition. Furthermore, the combination of benazepril and MMF conferred enhanced efficacy over monotherapies in the treatment of diabetic nephropathy.

Topics: Actins; Animals; Benzazepines; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Immunohistochemistry; Kidney; Kidney Function Tests; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Serum Albumin; Transforming Growth Factor beta1

Leflunomide (LEF) and benazepril have renoprotective effects on diabetic nephropathy (DN) through their anti-inflammatory and anti-fibrotic activities. This study investigated whether combined treatment using LEF and benazepril affords superior protection compared with the respective monotherapies.. Diabetes was induced with streptozotocin (STZ, 65 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 12 weeks with LEF (10 mg/kg), benazepril (10 mg/kg), or a combination of both. Basic parameters (body weight, fasting blood glucose level, and 24 h urinary protein excretion), histopathology, inflammatory [inflammatory cell infiltration (ED-1), monocyte chemoattractant protein-1 (MCP-1), and Toll-like receptor-2 (TLR-2)] and glomerulosclerotic factors [transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF)], and oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG) were studied.. Benazepril or LEF treatment significantly prevented body weight loss and 24 h urinary protein excretion induced by diabetes; combined treatment with LEF and benazepril further improved these parameters compared with giving each drug alone (all p < 0.01). Increased expression of inflammatory (MCP-1 and TLR-2) and glomerulosclerotic (TGF-β1 and CTGF) factors in diabetic rat kidney was reduced by treatment with either LEF or benazepril and was further reduced by the combined administration of the two drugs (p < 0.01). These effects were accompanied by suppression of urinary 8-OHdG excretion. There was no significant between-group difference in blood glucose level.. LEF treatment lessens DN, and combined treatment with LEF and benazepril provides synergistic effects in preventing DN.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Benzazepines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Synergism; Isoxazoles; Leflunomide; Male; Rats; Rats, Wistar; Treatment Outcome

Diabetic nephropathy (DN) is the leading cause of the end-stage failure of kidney, but the efficacy of currently available strategies for the prevention of DN remains poor. An activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), has been suggested to be a key step in the pathogenesis of DN. In the present study, we investigated the effect of Astragalus polysaccharide (APS), an aqueous extract from the Astragalus membranaceus roots, on gene expressions of NF-kappaB and an inhibitory protein of nuclear factor-kappaB (IkappaB) in experimental DN induced by streptozotocin in male Sprague-Dawley rats.. Rats with DN were treated with APS (1g/kg p.o.) or benazepril (1.5mg/kg p.o.), an angiotensin-converting enzyme inhibitor, using as positive control. The biochemical parameters such as blood glucose, plasma lipid and microalbuminuria were measured. Also, the mRNA level of NF-kappaB or IkappaB in renal cortex was determined using reverse transcription-polymerase chain reaction.. Eight weeks after the treatment, symptoms including shineless, bristly hair, polyuria, polydipsia, lethargy, physical inactivity, loss of body weight, kyphosis and decubitus position were ameliorated by APS. The levels of blood glucose, plasma lipid and microalbuminuria were lowered in APS-treated rats compared with control rats. The ratio of kidney weight over body weight was reduced and the renal function was improved after APS treatment. The mRNA level of NF-kappaB in renal cortex was decreased and IkappaB mRNA expression was raised by APS. These results suggest that APS has prophylactic and therapeutic effects on the progress of DN;. therefore, APS is helpful for the prevention and/or treatment of DN at early stage.

Topics: Animals; Astragalus Plant; Benzazepines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; I-kappa B Kinase; Kidney Cortex; Male; NF-kappa B; Phytotherapy; Polysaccharides; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin

Rhein and angiotensin-converting enzyme inhibitor (ACEI) have been reported to prevent the progression of diabetic nephropathy (DN). We further explore the unknown ability to induce renal-protection of rhein and ACEI combined therapy in DN compared with the therapeutic effects of single treatment of them by using db/db mouse of type 2 diabetes model.. db/db and db/m mice, 8 weeks of age, were divided into five groups according to the following treatments: (A) db/m, given saline treatment; (B) db/db, given saline treatment; (C) db/db, given rhein treatment (150 mg/kg/day); (D) db/db, given benazepril treatment (10 mg/kg/day); (E) db/db, given rhein (150 mg/kg/day) with benazepril (10 mg/kg/day). Body weight, plasma glucose, plasma lipid and 24 h urinary albumin excretion levels were measured every 4 weeks. Morphometry of renal tissue and immunohistology of transforming growth factor-beta1 (TGF-beta) and fibronectin were determined for all groups at the end of the treatment.. It was found that after treatment urinary albumin excretion was reduced after 4 weeks treatment in group E and after 8 weeks treatment in groups C and D, when compared to group B (p<0.05). Plasma creatinine levels dropped significantly for group E, compared with the diabetic control group by the end of the treatment period. Furthermore, after the treatment body weight, plasma glucose, cholesterol, triglyceride and low density lipoprotein all decreased in groups C and E compared to group B (p<0.05). Histological morphometric analysis revealed that the whole glomerular area and extracellular matrix area was significantly reduced in groups C, D and E compared to group B, at 20 weeks of age, an effect most pronounced in group E. Using immunohistochemistry, the expression of fibronectin and TGF-beta1 in groups C, D and E was found to have decreased compared to group B, after 12 weeks treatment, again the effect being more pronounced in group E.. There appeared to be a similar renal protective effect of rhein compared with benazepril in diabetic nephropathy. A combined therapy may offer a more beneficial complementary effect on kidney injury in db/db mice, as reflected by urinary albumin excretion, renal function and histological changes. Our findings suggest that a therapeutic approach that combines rhein with ACEI provides a more effective therapy for DN than does either agent alone.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Anthraquinones; Benzazepines; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enzyme Inhibitors; Fibronectins; Fluorescent Antibody Technique, Direct; Immunohistochemistry; Mice; Mice, Inbred C57BL; Random Allocation; Transforming Growth Factor beta; Triglycerides

To investigate the effects of Tangshenling Mixture (TSLM) and benazepril on rats with diabetic nephropathy (DN) and its mechanism.. Diabetic nephropathy was induced in rats by intraperitoneal injection of streptozotocin. Fifty-eight rats with DN were randomly divided into four groups: untreated group, TSLM-treated group, TSLM plus benazepril-treated group and benazepril-treated group. Another seven normal rats were included in normal control group. Then, rats in each group were accordingly given normal saline, TSLM, TSLM plus benazepril and benazepril orally for six weeks respectively. Blood and urine biochemical indexes, plasma atrial natriuretic factor (ANF), pathomorphology of renal tissue, transforming growth factor beta1 (TGF-beta1) and glucose transporter 1 (GLUT1) mRNAs in renal tissue were observed.. Both TSLM and benazepril could decrease urinary albumin excretion rates, creatinine clearance and ratio of kidney weight to body weight of the rats with DN as well as reduce the pathological damages of the renal tissues. TSLM could reduce the level of plasma ANF and the expression of GLUT1 mRNA, but had no significant effect on the expression of TGF-beta1 mRNA. Benazepril could reduce the expression of TGF-beta1 mRNA, but had no significant effect on plasma ANF and the expression of GLUT1 mRNA.. TSLM can reduce the pathological damages of renal tissues in rats with early-stage DN, and its mechanism may relate to decreasing the level of plasma ANF and the expression of GLUT1 mRNA which is different from that of benazepril. It seems that TSLM has synergetic effect with benazepril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drugs, Chinese Herbal; Glucose Transporter Type 1; Kidney; Male; Phytotherapy; Random Allocation; Rats; Rats, Wistar; Transforming Growth Factor beta; Transforming Growth Factor beta1

Excessive deposition of extracellular matrix (ECM) in the kidney is the hallmark of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting. The renal protective effect of these pathways on matrix accumulation has not been fully elucidated. The present study was undertaken to investigate the activity of matrix metalloproteinase-2 (MMP-2), the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) in kidney tissues of diabetic rats, and to explore the degradative pathway of type IV collagen (IV-C) and the renal protective effects of ACE inhibition-benazepril.. Twenty-four healthy male Wistar rats were divided randomly into normal control group (NC group), untreated diabetes mellitus group (DM group), and diabetes mellitus group treated with benazepril (DL group). The rat model of diabetes mellitus was induced by intraperitoneal injection of streptozocin (60 mg/kg). After the establishment of DM model, benazepril (10 mg.kg(-1).d(-1)) was given to the DL group for 12 weeks, and the same volume of water was given to the other two groups. At the end of 12 weeks, renal function was evaluated with 24-hour urinary protein (Upro), clearance of creatinine (Ccr), and blood urea nitrogen (BUN). MMP-2 activity was determined by gelatin zymography. The levels of MMP-2, TIMP-2 and collagen IV (IV-C) protein in the kidney tissue were assessed by immunohistochemistry. The gene expression of MMP-2 and TIMP-2 was measured by reverse transcription polymerase chain reaction (RT-PCR).. The levels of BUN, Upro and Ccr in the DM group were higher than those in the NC group. In the DM group, the mRNA, enzymatic activity and proteins of MMP-2 decreased, but the expressions of IV-C and TIMP-2 increased. All diabetes-associated changes in renal function and MMP/TIMP were attenuated after benazepril treatment with reduced IV-C accumulation.. The changes of MMP-2 and TIMP-2 expressions in kidney tissues of diabetes rats may contribute to the occurrence and progression of diabetic nephropathy. Benazepril could exert protective effects on diabetic nephropathy, owing to the upregulation of MMP-2 and downregulation of TIMP-2 expressions, which further inhibits the excessive deposition of extracellular matrix in the glomerulus.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Glucose; Body Weight; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney; Kidney Glomerulus; Male; Matrix Metalloproteinase 2; Organ Size; Rats; Rats, Wistar; Streptozocin; Tissue Inhibitor of Metalloproteinase-2

The accumulation of advanced glycation end products (AGE) is a key factor in diabetic nephropathy (DN). Pyridoxamine inhibits AGE formation and protects against type I DN. Herein we tested: (1) whether C57BL6 db/db mice as a model of established type II DN resembled patients treated with drugs which inhibit angiotensin II action; (2) whether pyridoxamine was effective as a single therapy; and (3) whether pyridoxamine would add to the benefit of angiotensin-converting enzyme inhibition (ACEi) by enalapril. In first set of experiments mice were treated with ACEi (benazepril) and an angiotensin II receptor blocker (valsartan) combination for 16 weeks after the onset of diabetes. In second group, mice with established DN were treated with pyridoxamine for 8 weeks. In a third set, mice with established DN were treated with pyridoxamine and enalapril combination for 16 weeks. Benazepril and valsartan combination partially prevented the development and progression of DN. Pyridoxamine treatment, as single therapy, decreased the progression of albuminuria and glomerular lesions. The combination of pyridoxamine with enalapril reduced both mortality and the progression of DN. In conclusion, (1) C57 BL6 db/db mice are a model of progressive type II DN; (2) The combination of pyridoxamine with enalapril decreased progression of type 2 DN and overall mortality. Thus, pyridoxamine could be a valuable adjunct to the current treatment of established type II DN.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Enalapril; Female; Glycation End Products, Advanced; Mice; Mice, Inbred C57BL; Mice, Obese; Pyridoxamine; Tetrazoles; Valine; Valsartan; Vitamin B Complex

The effects of benazepril on P42/44MAPK, angiotensin II expression in renal tissue and renal pathological change of the experimental diabetic rats were assessed and the possible mechanism of benazepril's renoprotective effect was explored. Adult male Wistar rats, 11-12 weeks age, weighing initially 160 to 200 g were randomly allocated into 2 groups: control group (A, n = 6) and experimental group (n = 12). Diabetic rats in experimental group were rendered diabetic by intraperitoneal injection of Streptozotocin (60 mg/kg body weight), and randomly subdivided into B group (diabetic control) and C group (diabetic rats treated with benazepril, 6 mg/kg every day). Studies were performed 8 weeks after induction of diabetes. Twenty-four h urine of every rat was collected to detect urine creatinine. Serum glucose concentration and serum creatinine were determined by collecting blood samples from the inferior vena cava. Body and kidney weight were recorded. Creatinine clearance (Ccr) and ratio of kidney weight to body weight were calculated. Plasma and renal tissue angiotensin II concentration was assayed by radioimmunoassay (RIA). The phospo-p44/42MAPK protein expression was detected by Western-blot. The results showed that benazepril had no significant effect on the blood glucose level in diabetic rats in two experimental groups. Ccr and ratio of kidney weight to body weight were increased in group B (P < 0.01) as compared with normal rats at the end of the 8th week. At the end of the 8th week, Ccr in group C was lower than that in group B (P < 0.01). The ratio of kidney weight to body weight in group C was lower than that in group B at the 8th week. There were glomeruli hypertrophy and slight or moderate mesangium proliferation in diabetic rats, while there was fragmentally proliferative mesangium in group C at the end of the 8th week. Renal tissue angiotensin II concentration was significantly increased in group B, while benazepril could significantly decrease the concentration of angiotensin II in renal tissue. The expression of the phospo-p44/42MAPK protein in group B was increased as compared with group A, while it was decreased in group C as compared with group B. P42/ 44MAPK pathway participated in the pathogenesis of diabetic nephropathy. Benazepril can eliminate high filtration of glomeruli, decrease proteinuria, and eliminate renal hypertrophy as well as renal destruction. Renoprotective effect of benazepril in diabetic rats may be partly related to th

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney Function Tests; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Protective Agents; Random Allocation; Rats; Rats, Wistar

Plasmin is an important factor in the degradation of extracellular matrix. In the study reported here we examined the expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (uPA), and uPA receptor (uPAR), as well as the relevance of such expression to the production of type IV collagen, a major component of extracellular matrix, in the renal tissue of rats with streptozotocin-induced diabetes. Because angiotensin II is involved in the synthesis of PAI-1 and uPA, we also examined the effect of benazepril, an angiotensin-converting-enzyme inhibitor, on the expression of PAI-1, uPA, and uPAR messenger RNAs (mRNAs) and type IV collagen protein. Rats with streptozocin-induced diabetes-some untreated and some treated with 30 mg/L benazepril-and nondiabetic control rats were sacrificed at 4, 12, or 24 weeks after induction of diabetes. We examined the expression of PAI-1, uPA, and uPAR mRNAs through the use of in situ hybridization and that of type IV collagen by means of immunohistochemical methods. In control rats, we detected weak signals for PAI-1, uPA, and uPAR mRNAs in glomeruli. Diabetic rats exhibited high levels of expression of PAI-1, uPA, and uPAR mRNAs and type IV collagen protein, mainly in mesangial cells. These mRNAs were synthesized in various renal cells (epithelial, mesangial, and endothelial cells and Bowman's capsule). Benazepril inhibited increases in all 3 mRNAs, especially in the mesangium; reduced type IV collagen expression; and attenuated mesangial expansion. Our results indicated that altered expression of PAI-1, uPA, and uPAR in diabetic nephropathy was associated with mesangial expansion and that the beneficial effects of ACE-I may be at least associated with such expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney; Male; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Urokinase-Type Plasminogen Activator

To study the effect of the Compound of traditional Chinese drugs and Benazepril on gene expression of renal endothelin and its receptor of experimental diabetic nephropathy(DN). To discove the mechanism of the compound of traditional Chinese drugs in treating DN.. Streptozotocin DN model was built and influenced with the compound of traditional Chinese drugs and Benazepril. The changes of Upro, Glu, HbA1C and (PT-PCR) mRNA expression levels of ET-1, ETA-R of the renal cortex were tested, and thus the histopathological character of the kidney was analysed.. The compound of traditional Chinese drugs and Benazepril have significant difference from normal saline in the improvement of Upro, Glu, HbA1C. The compound of traditional Chinese drugs have significant difference from Benazepril in the improvement of Glu, HbA1C. The mRNA expression level of ET-1, ETA-R of the renal cortex of DN model was raised. After influenced by the compound of traditional Chinese drugs and Benazepril, the over-expression level de-creased (still higher than normal control ones). The compound of traditional Chinese drugs were more effective than Benazepril to inhibit the proliferation of the stalk region and the third cells.. ET takes part in the process of diabetic glo-Merulosclerosis. Both the compound of traditional Chinese drugs and Benazepril can influence the expression quantity from the level of gene transcription of ET and its receptor. The compound of traditional Chinese drugs can not only reduce urinary albumin of DN, but also improve blood glucose, glycosylated hemoglubin. And it can inhibit nonenzymatic glucosylation of protein as well as the proliferation of the stalk region and the third cells.

Topics: Animals; Benzazepines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Drugs, Chinese Herbal; Endothelin-1; Gene Expression; Kidney Cortex; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger

To investigate the effects of angiotensin converting enzyme inhibitor (ACEI) on apoptosis and the expression of Fas and Fas-L in the kidney of diabetic rats.. Uninephrectomized Spraque-Dawley rats were used to induce diabetes by intraperitoneal injection of streptozotocin (65 mg.kg-1). Benazepril (10 mg.kg-1) was given daily by gavage from the next day of the induction to diabetes for 12 weeks. Apoptosis was evaluated by means of terminal-deoxynucleotidyl transferase mediated d-UTP nick end labeling (TUNEL). Flow cytometry and immunohistochemistry were used to detect the expression of Fas and Fas-L.. Compared with those in the kidneys of control group, apoptotic cells were more in number and the expression of Fas and Fas-L was higher in the diabetic kidneys (P < 0.05). The number of apoptotic cells and the level of expression of Fas and Fas-L were reduced by benazepril treatment (P < 0.05).. Angiotensin converting enzyme inhibitor benazepril showed some renal protective effect on diabetic nephropathy, partly through inhibiting apoptosis by down-regulating Fas and Fas-L expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Benzazepines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fas Ligand Protein; fas Receptor; Kidney; Male; Membrane Glycoproteins; Random Allocation; Rats; Rats, Sprague-Dawley