| Objective: Diabetic nephropathy is one of the main complication in advanced stage of diabetes mellitus .Activation of the transforming growth factor-beta (TGF-beta) system has been implicated in the pathological changes of diabetic nephropathy such as renal hypertrophy and accumulation of extracellular matrix (ECM) . The Smad family of proteins has recently been identified as a predominant signaling pathway by which TGF-B activates the transcription of several well-known TGF-B-inducible genes. Binding of TGF-6 to its type Ⅱ receptor and subsequent recruitment of the type I receptor result in the phosphorylation and activation of two receptor-regulated Smads (R-Smads) , Smad2 and Smad3. After associating with a common-Smad ( Co-Smad ) , Smad4, the Smad complex translocates into the nucleus where it cooperates with other transcription factors to coordinate the expression of target genes. Because diabetes results in the activation of the renal TGF-B system, the Smad pathway is probably activated in the diabetic state.Many studies show that the drugs of angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) can down-regulate the expression of TGF-β. Inorder to investigate the effect of benazepril and losartan on expression and locolization of TGF-B i ,Smad4 and Smad7 in kidney tissue of diabetic rat,we carried out this experiment.Methods: Healthy male Wistar rats were divided into four groups: randomly-normal control group (N,n=l 2),strepotozocin induced diabetic rats group (DM,n=12) , strepotozocin induced diabetic rats with benazepril treatment (DM-B,N=12) and strepotozocin induced diabetic rats with losartan treatment (DM-L,n=12) .The rats were sacrificed after treated for four and eight weeks.Mean aterial pressure,plasma glucose, kidney weight,body weight,urinary protein of twenty-four hours were observed,ratio of kidney weight and body weight were calculated.The levels of TGF-B, ,Smad4 and Smad7 mRNA were examined by RT-PCR.The locolizations and levels of TGF-B i ,Smad4 and Smad7 protein were examined by immunohistochemistry staining. PAS staining were used to analysis the pathology of kidney tissue.Results: l.By the end of 4 and 8 weeks, compared to normal control group, body weight decreased, kidney weight increased, plasma glucose , kidney weight/body weight, urinary protein of twenty-four hours were significantly increased in all diabetic rat groups,and the groups were also associated with marked glomerular extracellular matrix accumulation and mesangial expansion (PAS staining, 4W DM 0.1006±0.0010, DM-B 0.0576±0.0017, DM-L 0.0581±0.0004 vs N 0.0322±0.0009, P<0.0\; 8WDM0.1135±0.0050, DM-B 0.0592±0.0004, DM-L0.0603±0.0005 vs N 0.0332±0.0005, PO.01 ). TGF-fli ,Smad4 and Smad7 protein were locolized in normal kidney tissue. TGF- 6] protein were locolized in renal tubule interstitial. Smad4 and Smad7 protein were mainly locolized in glomerulus and renal tubular epithelial cells of renal cortex,scattered in renal tubular epithelial cells of renal medulla.The levels of TGF-B|,Smad4 and Smad7 mRNA were up-regulated as well as the expression of TGF- 6i,Smad4 and Smad7 protein in all diabetic rat groups(P<0.01). Compared to normal control group, mean aterial pressure in the DM group increased( PO.01 ) .However,mean aterial pressure ( mmHg ) in drug-using groups were not decreased (4W DM-B 109.6±4.6, DM-L 108.1±5.1 vs 107.3±2.0 , P>0.05-, 8W DM-B 110.0±4.9, DM-L109.2±5.0vsl08.1±3.0, />>0.05) .2. By the end of 4 and 8 weeks, compared to DM group,benazepril and losartan administration made all changes much better(P<0.0\) .3. Body weight, plasma glucose , mean aterial pressure ,kidney weight/body weight, urinary protein of twenty-four hours in benazepril and losartan administration groups showed no significant diffrences as well as glomerular extracellular matrix accumulation and TGF-B| ,Smad4 ,Smad7 mRNA and protein expression(7J>0.05).4. Body weight, plasma glucose , mean aterial pressure ,kidney weight/body weight, urinary protein of twenty-four hours by the end of 4 and 8 weeks in four groups showed no significant diffrences as well as glomerular extracellular matrix accumulation and TGF-... |
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