benazepril and Glomerulosclerosis--Focal-Segmental

To explore the intensity of inhibitory function of Shenkang injection (SKI), a Chinese herbal recipe, and benazepril on the proliferation of human glomerular mesangial cell (MC).. The effect of SKI and benazepril on the proliferation of human MC was observed by using the cultured MC in vitro and serum pharmacological assay.. Both SKI and benazepril could inhibit the proliferation of human MC, but in equal dosage consistency, SKI showed a better inhibitory effect than that of benazepril.. MC is the important target cell for the action of SKI, the inhibiting on proliferation might be one of the essential mechanisms of SKI in retarding glomerulosclerosis.

Topics: Animals; Benzazepines; Cell Division; Cells, Cultured; Drugs, Chinese Herbal; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Humans; Random Allocation; Rats

Although ATRA is a potent renoprotective agent, relatively little is known regarding the mechanisms of its action. The present study was designed to further elucidate the mechanisms of ATRA's action to GS rats and compare that with the beneficial effect of benazepril. Male SD rats weighting 160 to 200g were used in this study. GS was induced by unilateral nephrectomy and intravenous injection of adriamycin (6mg/kg). They were divided randomly 20 ones per group into GS group, GS treated with ATRA (20mg/kg/day) group, and GS treated with benazepril (10mg/kg/day) group. The other 20 ones were taken as sham-operation group, injected normal saline into caudal vein. 12weeks later, all rats were subjected to sacrifice. As expected, the GS group exhibited significant lower serum TP and Alb, and higher BUN, Cr and proteinuria than those of the sham group. Administration of ATRA or benazepril did ameliorate these above disorders of biochemical parameters in GS rats. Extensive renal damage was observed in the GS group, such as mononuclear infiltration, mesangial proliferation, focal segment glomerular sclerosis, and tubulointerstitial fibrosis. The pathological changes in both ATRA and benazepril group were alleviated remarkably. Semiquantitative GSI was used to evaluate the degree of GS in all groups. GSI was significantly higher in the GS group than in sham group. GSI decreased from 21.9+/-6.7 in the GS group to 6.9+/-2.8 in the ATRA group and 7.0+/-2.7 in benazepril group respectively. However, no significant difference in GSI between rats treated with ATRA and rats treated with benazepril was found. RT-PCR analysis revealed the renal expression of alpha-SMA mRNA was induced substantially in GS group as compared to sham group, which could be offset completely by ATRA or benazepril administration. However, expression level of alpha-SMA mRNA in GS rats treated with ATRA was identical to that in GS rats treated with benazepril. We also examined immunohistochemical staining for renal alpha-SMA, TGF-beta1, Col IV, and FN in this model. Weak staining was observed in some glomerulus, mesangial cells, and tubular interstitium of sham rats. Staining was markedly enhanced in the majority of glomerulus, mesangial cells, and tubular interstitium of untreated GS rats. Compared with untreated GS animals, intensity and extent of staining for renal alpha-SMA, TGF-beta1, Col IV, and FN were markedly reduced in glomerulus, mesangial cells, and tubular interstitium of GS rats treat

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Gene Expression Regulation; Glomerulosclerosis, Focal Segmental; Immunoenzyme Techniques; Male; Muscle, Smooth; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tretinoin

To investigate the protective effects of blocking rennin-angiotensin system (RAS) on the progression of renal injury in glomerulosclerosis, a glomerulosclerosis model was made for SD rats by unilateral nephrectomy and being injected with Adriamycin into caudal vein. The rats with glomerulosclerosis were randomly divided as ten per group into those without further treatment (group D) and those treated with Benazepril (group DB), Losartan (group DL), or sham-operation (group C), respectively. After 6 weeks of administration of Benazepril or Losartan, the mRNA expressions of TGF-beta1, Col IV, Fn, ET-1 and iNOS in renal cortex were measured by RT-PCR. Besides, the expressions of TGF-beta1, ET-1 and iNOS at protein level were detected by Western blotting and the concentrations of Col IV and Fn were analyzed with immunohistochemistry respectively. Results showed that the rats in group D appeared as obvious proteinuria, hypoalbuminemia and hypercholesterolemia, which had a significant difference compared with group C (p < 0.05), and most of their mesangiums were detected with cellular proliferation and significant increasing for extracellular matrix. Renal cortex TGF-beta1, Col IV, Fn, ET-1 and iNOS in rats of group D were increased by 3.59, 2.57, 2.21, 2.58 and 3.28 times at mRNA level, and by 2.60, 1.40, 0.75, 1.83 and 2.15 times at protein level, respectively, compared with group C. When the animals were treated with Benazepril (group DB) or Losartan (group DL), however, the biochemical and pathological damages were significantly recovered, and protein expressions of TGF-beta1, Col IV, Fn, ET-1 and iNOS were also significantly diminished (p < 0.05). This study suggested that blocking RAS using Benazepril or Losartan can have protective effects on the renal injury in glomerulosclerosis by down-regulating the expressions of TGF-beta1, Col IV, Fn, ET-1 and iNOS.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Base Sequence; Benzazepines; Collagen Type IV; DNA, Complementary; Endothelin-1; Fibronectins; Glomerulosclerosis, Focal Segmental; Kidney; Losartan; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

The effects of the combined use of angiotensin converting enzyme inhibitor (ACEI) benazepril and angiotensin II type 1 receptor antagonist (AT1RA) valsartan on apoptosis and the expression of apoptosis-related proteins Fas and FasL in the kidney of rats with adriamycin-induced nephritic glomerulosclerosis was investigated. Uninephrectomy and the injection of adriamycin induced the rat model of glomerulosclerosis. Benazepril (6 mg/kg), valsantan (20 mg/kg), or benazepril (3 mg/kg) plus valsantan (20 mg/kg) was respectively delivered daily by gavage to the rats in three treatment groups for 12 weeks. Apoptosis was examined by means of terminal-deoxynucleotidyl transferase mediated d-UTP nick end labeling (TUNEL). Immunohistochemistry was adopted to detect the expression of Fas and FasL. Software of pathological analysis quantitated the levels of Fas and FasL. The results showed that as compared with those in the control group, the kidneys in the model group had more severe glomerulosclerosis, much more apoptotic cells and higher levels of expression of Fas and FasL. The degree of glomerulosclerosis, the number of apoptotic cells and the levels of expression of Fas and FasL were reduced by benazepril and valsartan. The combined use of benazepril and valsartan had the best therapeutic effect. It was concluded that benazepril and valsartan could suppress the excessive apoptosis of kidney cells by lowering the expression of the apoptosis-related proteins Fas and FasL, so as to postpone the process of glomerulosclerosis. The combined use of benazepril and valsartan has better therapeutic effect.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Benzazepines; Doxorubicin; Drug Therapy, Combination; Fas Ligand Protein; fas Receptor; Glomerulosclerosis, Focal Segmental; Kidney; Male; Membrane Glycoproteins; Random Allocation; Rats; Rats, Sprague-Dawley; Tetrazoles; Tumor Necrosis Factors; Valine; Valsartan

There is little information on the significance of angiotensin-converting enzyme (ACE) genotypes and medical treatments in children with primary focal segmental glomerulosclerosis (FSGS).. A multicenter retrospective study was performed on the role of ACE genotypes and medical treatments in 43 Japanese children with FSGS (20 males and 23 females), including 17 children who progressed to end-stage renal failure during the mean observation period of 6.9 +/- (SD) 5.0 years.. The incidence of the D allele of the ACE gene was higher in the whole group of 43 children with FSGS and in a subgroup of 28 steroid-resistant FSGS children (p < 0.05) than in the 130 children of the healthy control group (0.48, 0.48, and 0.33, respectively). ACE genotypes did not affect renal survival in the whole FSGS group nor in the steroid-resistant subgroup. Among the 28 steroid-resistant children, treatment with ciclosporin was effective in delaying the development of end-stage renal failure (p = 0.044), independently of other treatment regimens.. The present study of Japanese children with FSGS showed that the D allele of the ACE gene is associated with the development of FSGS, but not associated with the progression of FSGS which was greatly ameliorated with ciclosporin, irrespective of ACE genotypes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Benzazepines; Captopril; Child; Disease Progression; Drug Resistance; Enalapril; Female; Glomerulosclerosis, Focal Segmental; Humans; Incidence; Japan; Kidney Failure, Chronic; Male; Peptidyl-Dipeptidase A; Prednisolone; Proteinuria; Regression Analysis; Retrospective Studies; Survival Rate

The superiority of renin-angiotensin system (RAS) blockade in providing renoprotection has been attributed to class-specific blood pressure "(BP)-independent" mechanisms. However, the conventional BP measurement methodology on which such conclusions are based is inherently limited for an accurate assessment of the fluctuating ambient BP profiles. The present studies were undertaken to rigorously examine the relationship of renoprotection to the antihypertensive effects of RAS blockade using chronic BP radiotelemetry in the 5/6 renal ablation model.. Rats with 5/6 renal ablation received either no treatment, the angiotensin-converting enzyme inhibitor benazepril at a dose of 25, 50, and 100 mg/L; or the angiotensin receptor antagonist losartan at a dose of 50, 120, and 180 mg/L of drinking H2O; and were followed for seven weeks.. Glomerulosclerosis (GS) at sacrifice (approximately 7 weeks) demonstrated a close correlation with the average systolic BP in untreated (r = 0.76, N = 20), benazepril-treated (r = 0.80, N = 33), losartan-treated (r = 0.83, N = 32), or all animals combined (r = 0.81, N = 85, P < 0.0001 for all correlations). The slope of the relationship between GS and BP (percentage of increase in GS/mm Hg increase in BP) in untreated rats (0.7 +/- 0.14) was not significantly altered by either benazepril (0.96 +/- 0.13) or losartan (0.60 +/- 0.08), indicating that RAS blockade, by either agent, resulted in renoprotection that was proportionate to the achieved BP reductions.. These data demonstrate that RAS blockade provides renoprotection in the rat remnant kidney model of progressive GS, primarily through "BP-dependent" and not "BP-independent" mechanisms.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Glomerulosclerosis, Focal Segmental; Kidney; Losartan; Male; Nephrectomy; Radio Waves; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Telemetry

Angiotensin converting enzyme inhibitors have uniformly been shown to prevent the development both of proteinuria and of glomerulosclerosis in rats with a remnant kidney. Conversely, dihydropyridine calcium antagonists (DCA) have failed to demonstrate such a benefit in spite of causing an equivalent reduction in blood pressure.. To test the hypothesis that concomitant administration of an angiotensin converting enzyme inhibitor and a DCA would lead to a smaller increase both in proteinuria and in glomerulosclerosis relative to that caused by administration of a DCA alone at similar levels of blood pressure.. Experiments were carried out using Sprague-Dawley rats that had been subjected to five-sixths renal ablation. Animals were allocated randomly to one of four groups: control (no treatment), amlodipine (A rats), benazepril (B rats), or a combination of benazepril and amlodipine (B + A rats). We implanted intraperitoneal sensors for telemetric monitoring of the animal's blood pressure. Other parameters measured at baseline included proteinuria and inulin clearance. After approximately 7 weeks all of the parameters were remeasured and animals killed for morphologic assessment of the kidney.. The B + A rats had lower levels of proteinuria than did the rats in group A (21 +/- 12 mg/day for B + A rats versus 59 +/- 24 mg/day for A rats, P < 0.05). The degree of glomerulosclerosis in the B + A rats was also reduced markedly compared with that in A rats (12 +/- 4% for B + A rats versus 43 +/- 12% for A rats, P < 0.05). Moreover, the results on proteinuria and glomerulosclerosis of B + A rats were similar to those for B rats. These differences could not be explained totally in terms of differences in blood pressure control (144 +/- 12 mmHg in A rats versus 132 +/- 13 mmHg in B + A rats, NS).. The results were consistent with the observation that a combination of benzepril and amlodipine provides additional protection against renal injury compared with that provided by amlodipine alone. The mechanism for this benefit is not known.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Calcium Channel Blockers; Disease Models, Animal; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Kidney; Male; Nephrectomy; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley