| Objective: To observe the protective effects of Yu Xia Capsule on renal fibrosis in spontaneous hypertensive rats(SHR)and its potential mechanism.Methods: Twenty-eight 14 weeks old male SHRs,weighting 230±20 g were randomly divided into three administered groups due to the dose of Yu Xia capsule(0.6,0.3 and0.15 g·kg-1·d-1),and SHR model group(0.5% sodium carboxymethyl cellulose,0.5%CMC-Na,5 m L·kg-1·d-1).WKYs of the same age were set as normal control group(0.5% sodium carboxymethyl cellulose,0.5% CMC-Na,5 m L·kg-1·d-1,n=7).After 2weeks adaptive feeding,all rats were gavaged with these dosages for 10 weeks.SBP and DBP were measured by non-invasive tail arterial blood pressure analysis system before and every 2 weeks after the drug administration.Urine was collected before and 3,5 and 8 weeks after the drug administration and measured the urine volume and urinary albumin(U-m ALb)content.After the last administration,body weight,left and right kidneys were weighed and kidney weight index was calculated respectively.All rats' blood was taken through abdominal aorta to obtain serum and plasma.The levels of serum ?2-microglobulin(?2-MG),serum creatinine(Scr)and blood urea nitrogen(BUN)were measured by automatic biochemical analyzer.The content of angiotensin II(Ang II)in blood plasma and renal tissue were measured by enzyme linked immunosorbent assay(ELISA).The primary pathologic changes of kidney were observed by HE staining,and Masson staining was used to observe the collagen deposition.The positive expressions of TGF-?1 and NF-?B in kidney were measured by immunohistochemistry.The expressions of TGF-?1 m RNA were detected by real time PCR.The expressions of ERK1/2?MMP-9?NF-?B?p-ERK1/2?P38?p-P38?p-Smad2/3?Smad2/3?Smad4?Smad7?TGF-?1 and TIMP-1 proteins in kidney were detected by Western blot.Results:(1)Compared with WKY,the SBP and DBP of SHR model group were significantly increased(P<0.01),and the SBP and DBP were differently decreased after administration of Yu Xia capsule(P<0.05 or P<0.01),and the high dose group decreased significantly.(2)Compared with WKY,there was no significant change in urine volume before and after administration of SHR.Compared with SHR,the volume of urine of rats in each Yu Xia capsule dose group was increased after administration of 3W,5W and 8W(P<0.01).(3)The kidney weight index of SHR group was significantly higher than that of WKY group(P<0.01),and those in all drug-treated groups were lower than that of SHR.(4)Compared with WKY,the levels of U-m ALb??2-MG?Scr and BUN were significantly increased in SHR(P<0.01),after the treatment,those in all drug-treated groups were notably decreased.(5)The content of Ang II in renal tissue and plasma of SHR group was significantly higher than that of WKY group(P<0.01),whereas those in all drug-treated groups were decreased significantly(P<0.01).(6)HE and Masson staining showed that the renal tubules were significantly atrophic,basement membrane of glomerular were proliferated,and collagen deposition was appeared in the renal interstitium in SHR,while the pathological changes were significantly improved in each treatment group.(7)The protein and positive expressions of TGF-?1 and NF-?B in kidney were markedly up-regulated in SHR(P<0.01),while the positive expression in each administration group was apparently down-regulated in contrast to that in SHR group(P<0.05 or P<0.01).(8)RT-PCR results showed that the expression of TGF-?1m RNA of SHR group was significantly higher than that of WKY group(P<0.01),and each administration group was significantly lower than SHR group(P<0.05 or P<0.01).(9)The expression levels of MMP-9?NF-?B?p-ERK1/2?P38?p-P38?p-Smad2/3?Smad4?Smad7?TGF-?1 and TIMP-1 proteins in kidney were obviously up-regulated with the expression of Smad7 down-regulated in SHR(P<0.01).Nevertheless drug treatment could markedly down-regulated the expressions of MMP-9 ? NF-?B ?p-ERK1/2?P38?p-P38?p-Smad2/3?Smad4?Smad7?TGF-?1 and TIMP-1 proteins and the expression of Smad7 was significantly increased(P<0.05 or P<0.01).Conclusion: Chinese traditional medicine medicine Yu Xia capsule has protective effect against renal fibrosis in spontaneous hypertensive rats,and it demonstrates dose-dependent manner in a certain range.Its mechanism may be related to decreasing blood pressure,promoting diuresis,reducing the content of Ang II,restraining over-activated TGF-?1/Smads signal pathway and regulating of P38/MAPK and ERK/MAPK relative pathways. |
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