Effects of benazepril on cardiac fibrosis in STZ-induced diabetic rats.
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The present study was designed to explore the roles of MMP-2/TIMP-2 in cardiac fibrosis and to study the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI) on cardiac remodelling in streptozotocin(STZ)-induced diabetic rats.Male Wistar rats were randomly divided into three groups: a normal control group (NC), a diabetes mellitus-untreated group (DM) and a diabetes mellitus benazepril-treated group (DB). Diabetes mellitus was induced in the DM and DB groups by intraperitoneal injection of streptozotocin (60 mg/kg). DB rats were treated with benazepril 10 mg/kg/day for 12 weeks by remedial perfusing of the stomach. In the DM group, compared with the NC group, the gene and protein expression of MMP-2 decreased while the TIMP-2 gene and protein expression increased in heart tissues, along with a markedly cardiac collagen deposition.All the above changes were attenuated by benazepril treatment in the DB group.The imbalance of MMP-2 and TIMP-2 expressions in heart tissues might participate in interstitial fibrosis in diabetic myocardiopathy. Benazepril may ameliorate cardiac fibrosis partly by regulating the MMP-2/TIMP-2 system.Keywords:
Benazepril
Intraperitoneal injection
Cardiac Fibrosis
Objective To investigate the effects of benazepril on connective tissue growth factor(CTGF)expression in myocardial tissue of streptozotocin(STZ)-induced experimental diabetic rats and its mechanism. Methods A total of 34 Wistar rats were enrolled in the study, 10 of them were set as normal controls, others were used to set up the diabetes mellitus models by injecting STZ, and then equally divided into benazepril-treated group and untreated group. Blood glucose and Tcho levels levels were determined, myocardial AngⅡ was detected by immunoradiometry and myocardial CTGF mRNA was assayed by RT-PCR after 12 weeks. Results Blood glucose and Tcho increased significantly in untreated group, the levels of myocardial AngⅡ and CTGF mRNA expression were higher than those in normal control and benazepril-treated group (P0.01). Conclusion Long lasted hyperglycemia can lead to the over-expression of CTGF mRNA in the myocardial tissue of diabetic rats. Benazepril may partly suppress it and decrease significantly the myocardial injury of diabetic rats by reducing the level of myocardial AngⅡ.
Benazepril
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Pioglitazone has been demonstrated to have beneficial effects on cardiovascular outcomes. However, little is known about its effect on cardiac remodeling associated with diabetic nephropathy. Therefore, this study was designed to study the effects of pioglitazone on cardiac fibrosis and hypertrophy in a rat model of diabetic nephropathy. For this purpose, male Wistar albino rats were randomly assigned into 4 groups (n = 10 per group): normal (N) group, diabetic (D) group, diabetic nephropathic (DN) group received an equal amount of vehicle (0.5% carboxy methyl cellulose), and diabetic nephropathic group treated by oral administration of pioglitazone (10 mg/kg per d) for 4 weeks. Diabetic nephropathy was induced by subtotal nephrectomy plus streptozotocin (STZ) injection. The results revealed that DN rats showed excessive deposition of collagen fibers in their cardiac tissue, along with a marked myocyte hypertrophy. This was associated with a dramatic upregulation of cardiac transforming growth factor-β1 (TGF-β1) gene. Furthermore, the gene expression of matrix metalloproteinase 2 (MMP-2) decreased, while the gene expression of tissue inhibitor of metalloproteinase 2 (TIMP-2) increased in the hearts of DN rats. In addition, enhanced lipid peroxidation and myocardial injury, evidenced by a significant increase in their serum creatine kinase-MB level were observed in DN rats. All these abnormalities were ameliorated by pioglitazone administration. Our findings suggest that upregulation of cardiac TGF-β1 gene along with the imbalance between MMP-2 and TIMP-2 expressions is critically involved in cardiac fibrosis associated with diabetic nephropathy. Pioglitazone can ameliorate cardiac remodeling by suppressing the gene expression of TGF-β1 and regulating the MMP-2/TIMP-2 system.
Pioglitazone
Cardiac Fibrosis
Diabetic Cardiomyopathy
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AIM:To observe the effects of exendin-4 on the expression of matrix metalloproteinase-9(MMP-9) and tissue inhibitor of metalloproteinase-1(TIMP-1) in the renal tissue of type 2 diabetic rats. METHODS:The rat model of type 2 diabetes mellitus was set up by a combination of high fat diat and low dose streptozotocin(STZ). The diabetic rats were randomly divided into 4 groups :diabetes mellitus group(DM group),low dose of exendin-4 group(EL group),middle dose of exendin-4 group(EM group),high dose of exendin-4 group(EH group). Normal control group(NC group) was also established. After 6 weeks,the expression of MMP-9 and TIMP-1 in renal tissue was measured by immunohistochemistry. RESULTS:The expression of MMP-9 and TIMP-1 in DM group was higher than that in NC group(P0.01),while the expression of MMP-9 and TIMP-1 in all doses of exendin-4 groups was lower than that in DM group(P0.01). CONCLUSION:Exendin-4 has some renoprotective effect on type 2 diabetic rats,partly through down-regulating the expression of MMP-9 and TIMP-1.
Matrix metalloproteinase 9
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【Objective】 To observe the effects of Valsartan on expression of MMP-9/TIMP-1 in renal tubular epithelial cells of diabetic nephropathy rats,elucidate the possible renal-protective mechanisms of Valsartan.【Methods】 Thirty male Wistar rats were randomly divided into 3 groups: normal control group(n =10),diabetic model group(n =10),and Valsartan treatment group(Valsartan 30 mg/kg·d,n =10).Five rats of each group were killed respectively at 8,16 weeks.The pathologic change and expressions of ILK and MMP-9/TIMP-1 in renal tubular epithelial cells were detected.【Results】 Comparing with the control group,renal tubular-interstitial lesions in the diabetic model group is significantly aggravated,the TGF-β1,MMP-9,TIMP-1 expressions elevated while the MMP-9/TIMP-1 ratio declined.The changes mentioned above in the Valsartan treatment group is significantly smaller than in diabetic model rats.【Conclusions】 MMP-9/TIMP-1 imbalance is one possible factor in the progress of renal interstitial fibrosis in diabetes mellitus.Valsartan can improve the process of renal tubular-interstitial lesions by regulating MMP-9/TIMP-1 level.
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Perindopril
Cardiac Fibrosis
Myocardial fibrosis
Diabetic Cardiomyopathy
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The changes in matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expressions were examined in the kidneys of diabetic rats to investigate the degradative pathway of collagen type IV (C-IV) and the protective effects of pioglitazone on an experimental model of diabetic nephropathy.In 54 SD rats used in our study, 18 served as normal controls. Diabetes mellitus was induced in 36 age- and weight-matched rats by intraperitoneal injection of streptozotocin (70 mg/kg); 18 of the diabetic rats were allocated at random to receive pioglitazone [20 mg.kg(-1).d(-1)] in their drinking water and 18 served as diabetic controls. Rats were killed after 2, 4, or 8 weeks of treatment. Kidneys were examined pathomorphologically and the expressions of MMP-2, MMP-9, and C-IV were analyzed by immunohistochemistry, and the results were quantified by image analysis techniques.Diabetes mellitus was associated with a decrease in the expression of MMP-2 in the glomeruli (P < 0.05, vs control). By contrast, MMP-2 expression in the interstitium increased, but not significantly (P > 0.05, vs control). The expression of MMP-9 did not show any change when comparing the three groups (P > 0.05, vs control). STZ-diabetic rats were also associated with an increase in the expression of C-IV in the glomeruli and the interstitium (P < 0.05, vs control). All diabetes-associated changes in MMP-2 expression were attenuated by pioglitazone treatment in association with reduced C-IV accumulation.These results indicate that a decrease in MMP-2 expression in the glomeruli of diabetic rats may lead to impairment of C-IV degradation and contribute to the matrix accumulation in diabetic nephropathy. Pioglitazone treatment, which can attenuate the decrease of glomerular MMP-2 and the increase of C-IV degradation, has curative effects on diabetic nephropathy.
Pioglitazone
Intraperitoneal injection
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Objectives] To investigate the effect of Losartan, a blocker of angiotensinⅡtype 1 receptor, on the expression of tissue inhibitor of metalloproteinase 2 (TIMP2) mRNA in the diabetic kidneys. The male Wistar rats were divided into 3 groups, the controls (n=11), the diabetic rats without any therapy (n=11), and the diabetic rats treated with Losartan (n=9) The diabetic model was made by the intraperitoneal injection of streptozotocin At the end of the 18th week, the kidneys were taken out from all the rats to measure the expression of TIMP2 mRNA by RT PCR, and observe the glomerular basement membrane thickening and mesangial matrix density (mesangial area/mesangial area) by electronic microscope At the same time, the 24 hours of urine was collected to measure the levels of the albumin (UAE) The expression of renal TIMP2 mRNA in the diabetic rats without any therapy (0 73±0 37) was higher than that in controls (P0 05), and in the diabetic rats treated with Losartan (0 34±0 17) lower than in the diabetic rats without any therapy (P0 05) UAE in the diabetic rats without any therapy (2 18 mg±1 98 mg) was higher significantly than that in controls (0 41 mg/d±0 47 mg/d, P0 05), and in the diabetic rats treated with Losartan (0 65 mg/d±0 89 mg/d) lower than in the diabetic rats without any therapy (P0 05) The glomerular basement membrane thickening (531 6 nm±107 6 nm) and the mesangial matrix density (56±7) in the diabetic rats without any therapy were higher significantly than those in controls (P0 05), and in the diabetic rats treated with Losartan (glomerular basement membrane thickening 316 6 nm±33 3 nm, mesangial matrix density, 35±7) lower than in the diabetic rat without any therapy (P0 05).[Conclusions] The expression of TIMP2 mRNA is increased significantly in diabetic kidneys Losartan can prevent the development of diabetic nephropathy, also decrease the expression of TIMP2 mRNA in diabetic kidneys Our data suggest that TIMP2 may play a role in the development of diabetic nephropathy
Intraperitoneal injection
Glomerulosclerosis
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Objective To investigate the effect of aminoguanidine on myocardial interstitial fibrosis and cardiac function in diabetic rats,and explore the mechanism of the actions.Methods Thirty male SD rats were randomly divided into 3 groups: normal control,STZ-induced diabetic rats,and diabetic rats treated with aminoguanidine.After 12 weeks,hemodynamics,advanced glycation end products(AGEs) in serum and values of collagen content,the expression of connective tissue growth factor(CTGF) mRNA and protein in the left ventricular tissue were measured.Results Compared with the control,AGEs fluorescence of serum(7.21±2.2 vs 2.63±0.62,P0.01),collagen content(16±3% vs 12±2%,P0.01),the expression of CTGF mRNA(0.077±0.0037 vs 0.0102±0.0034,P 0.01) and protein(0.51±0.01 vs 0.34±0.02,P 0.01) of myocardium were significantly increased in the diabetic group.The cardiac function was significantly lower in the diabetic group than in the control group.However,the above-mentioned abnormalities were obviously attenuated by administration of aminoguanidine.Conclusions AGEs play an important role in myocardial interstitial fibrosis of diabetic rats.Aminoguanidine can reverse the myocardial interstitial fibrosis and improve the cardiac function by inhibiting the formation of AGEs and down-regulating the over-expression of CTGF.
Myocardial fibrosis
Diabetic Cardiomyopathy
Cardiac Fibrosis
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Objective To investigate the effects of benazepril on expressions of matrix metallopro teinase-2, tissue inhibitor of metalloproteinase-2 and collagen IV (C-IV) in the kidney of diabetic rats. Methods Forty Sprague -Damly rats were randomly divided into three groups: the control group (C group), diabetes mellitus group (DM group) and diabetic group treated with benazepril (10mg/kg)(DB group). Eight weeks later, expression of MMP-2, TIMP-2 and C-IV in the kidney tissure was determined by immunohistochemistry method (SP)and RT-PCR. Results Compared with C group, expressions of protein and mRNA MMP-2 significantly reduced in the glomeruli,while expressions TIMP-2 and C-IV were increased in the DM group (P0.01). Meanwhile, the pathologic changes of the glomeruli were serious in DM group. The abnormal expressions of these proteins, mRNA and pathologic changes were dramatically improved in diabetic rats by benazepril treatment (P0.01). Conclusion Benazepril can exert protective effects on diabetic nephropathy, partly through upregulating MMP-2 and decreasing TIMP-2, C-IV accumulation in renal cortex.
Benazepril
Matrix metalloproteinase 9
Renal cortex
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Objective: To investigate the effects of rosiglitazone on the expression of matrix metalloproteinases-2,9(MMP-2,MMP-9)and collagen IV(C-IV) in renal cortex of diabetic rats. Methods: Forty Sprague -Dawley rats were randomly divided into 3 groups:normal control group (C group),diabetes mellitus group(DM group)and rosiglitazone-treated diabetes mellitus group(DR group). Diabetic model was induced by streptozocin(STZ), and the rats in DR group received rosiglitazone through stomach perfusion.The expression of MMP-2,MMP-9 and C-IV in the renal cortex was studied by immunohistochemistry. Changes of glomerulus were observed by using light microscope and electron microscope in three groups. Results: Compared with those in C group,the expression of MMP-2,MMP-9 in renal cortex was lower ,while that of C-IV was higher(P 0.01). The pathologic changes of glomerulas were significantly serious in DM group . The pathologic changes in DR group were improved by streptozocin treatment(P 0.01). Conclusion: MMP-2 and MMP-9 play an important role in the fomation of diabetic extracellular matrix. Rosiglitazone has protective effects on the kidneys of diabetic rats partly through upregulating MMP-2 and MMP-9 and decreasing C-IV accumulation in renal cortex.
Rosiglitazone
Streptozocin
Renal cortex
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