Combination Effects Of Moxonidine And Lotensin On The Course Of Adrismycin-induced Nephropathy

Objective and background:Tubulointerstitial fibrosis(TIF) is a common pathological featuresof most end-stage kidney disease. The accumulation of extracellularmatrix(ECM) resulting from the unbalance of synthesis and degradationis the main cause of TIF. Numbers of clinical pathology observationshave shown that tubulointerstitial injury plays more important role thanglomerular damage on renal failure .At present, effective therapy hasbeen looking for treatment of chronic renal failure except vicarioustreatment and renal transplantation. And vicarious treatments such ashemodialysis and peritoneal dialysis have side effect and the pathologiclesions can not be returned. The donor for transplantation was notenough, and the patients have to suffer serious rejection with it. Only afew people can accept the therapy because of the expensive charge. Sothe mechanisms of new therapy in TIF should be studied. In variousoutbreak mechanism the latent function of the sympathetic nerves cannot be neglected. The great function of the sympathetic nerve is not onlythe result of kidney disease but also the promote factor in the kidneydisease developing. The great activity of sympathetic nerve can damagedirectly the kidney while it can active the system of Noradrenaline(NE)and AngiotensinII(AngⅡ) so that the density of AngⅡ is increased inthe blood. The AngⅡ can be in conjunction with the various factors toresult the kidney fiber such as transforming growth factor beta(TGF-β1),Matrix metalloproteinase-1(MMP-1) and tissue inhibitor ofmetalloproteinase-1(TIMP-1) that they can cause tubulointerstitialfibrosis. In the course of the kidney disease developing, the expressionof factors to make TIF will be increased;the expression of factors toinhibit TIF will be relatively reduced. Therefore the synthesis anddegradation of ECM will be unbalance. The quality of ECM will beincreased. The TIF will get more serious .In last the kidney functioncrock up in last phase. The study was to investigate the combinationeffects of Moxonidine(Mox) and lotensin(Lot) in Adrismycin-inducedrats by the experiment zoology method. The renal pathomorphism,transforming growth factor beta(TGF-β1) matrixmetalloproteinses-1(MMP-1), Tissue inhibitor ofmetalloproteinases-1(TIMP-1) were examined. It provides science basistwo kinds of medicine treat kidney disease commonly in the clinic.Methods:1, Select 50 healthy male wistar rats. After a week of adaptive feed, therats were randomly divided into five groups: model group(Mod),moxonidine treatment group(Mox) lotensin treatment group(Lot),moxonidine and lotensin treatment group(Mox+Lot) and controlgroup(Con). The rats received first-intravenous injection of adrismycinto induce rats model with renal fibrosis. The control group receivedfirst-intravenous injection of 0.9% Nacl. Every group consisted of 10rats. The experiment term was 12 weeks.2, The proteinuria was detective at four. Eight and twelve weeks. Bythe end of twelve weeks, Blood pressure was measured in every rat, theblood sample were collected and Serum Creatinine, Noradrenaline(NE),AngiotensinⅡ(AngⅡ)were tested.3, The kidney pathomorphism was investigated at the end ofexperiment.4, Immunohistochemistry staining was used for expression of TGF-β1,MMP-1, TIMP-1 respectively.5, In situ hybridization was used for expression of TGF-β1mRNA,MMP-1 mRNA, TIMP-1mRNA respectively.Results:1, General circumstance and bio-chemical index: After about twoweeks, the rats showed bad appetite,Light weight and dropsy. Part ofrats appeared to lose hair in the model group and the treatment group.Compared with the Con group the urine albumin excretion wassignificantly increased(p<0.01)at the end of four, eight and twelveweek and along with time change it got more and more in the Modgroup. Compared with Mod group the urine albumin excretion wassignificantly decreased in the treatment groups (p<0.01), Comparedwith Mox or Lot group the urine albumin excretion was significantlyreduced in Mox+Lot group (p<0.01). Compared with Con group serumcreatinine was slightly increased (p > 0.05)and the mean arterialpressure was significantly gone up in the Mod and treatment group (p<0.01).Compared with Con group the indices NE and AngⅡ in theplasma were significantly increased (p<0.01) in the Mod group;compare with Mod or Lot group the indices NE and AngⅡ weresignificantly decreased in Mox+Lot group (p<0.01,p<0.01).2, Pathology: The renal tissue were stained with HE and MassonThere was no change in Con group. But in Mod group interstitialmacrophage and monocyt infiltration. Renal tubular atrophy, emphraxisor expand were shown. The number of glomeruli reduced markedly andthe area of glomeruli decreased. The renal capsule adhered or expanded.Fibrous tissues proliferated around the renal capsule. While the lesionsin treatment groups were slighter than that in Mod group. Pathologicimage analysis shows: compared with Con group In the Mod the meanvolume of glomeruli was reduced markedly (p<0.01), the renal tubularwas damaged significantly(p<0.01), the area of fibrosis was expandedmarkedly(p<0.01). Compared with the Mod group the area of fibrosisin Mox, Lot, Mox+Lot groups were decreased. The area of fibrosis inMox+Lot group was decreased than that of the Mox or Lot group (p<0.01). It means Moxonidine and Lotensin can inhibit fibrosis inobstructive nephropathy. Among them the inhibit fibrosis in theMox+Lot group was strongest.3, The expression, distribution and semi-quantitative analysis ofTGF-β1 with immunohistochemistry and suit hybridization: It wasshown a weak expression of TGF-β1 while in other groups theexpression of TGF-β1 in protein and its mRNA increased. They can beseen in renal tubular epithelial cell interstitial cell and glomeruli .Amongthem the expression of TGF-β1 in protein and its mRNA. In Mod groupwas higher than that in Con group(p<0.01).Compared with the Modgroup ,the expression of TGF-β1 in Mox,Lot, Mox+Lot groups weredecreased markedly(p<0.01). Compared with the Mox or Lot group theexpression of TGF-β1 was decreased markedly in Mox+Lot group (p<0.01) .It means that Moxonidine and Lotensin can inhibit the expressionof TGF-β1 in protein and mRNA level in obstructive kidney. Amongthem, The inhibition of Mox+Lot group was better than that of Mox orLot group alone.4, The expression, distribution and semi-quantitative analysis ofMMP-1 and TIMP-1 in protein and mRNA: In Con group the expressionof MMP-1 and TIMP-1 in protein and mRNA were weak on renaltubular epithelial cell and glomeruli. While in Other groups all of themincreased significantly. They can be shown in renal tubular epithelialcell, interstitial cell and glomeruli. Among them the expression ofprotein and mRNA of TIMP-1, MMP-1 in Mod group were higher thanthat in con group (p<0.05), but TIMP-1 increased more than MMP-1,soit means there was unbalance of MMP-1/TIMP-1 in obstructivekidney .For MMP-1, there are no significantly difference in the threetreatment groups compared with the Mod group (p>0.05);For TIMP-1the expression in Mox, Lot, Mox+Lot groups decreased markedlycompared with the Mod group (p<0.01).The expression of TIMP-1 inMox+Lot group was decreased markedly than that of TIMP-1 in Moxand Lot(p < 0.01).It means Moxonidine and Lotensin adjust theunbalance of MMP-1/TIMP-1.The combination effects of Mox and Lotis the strongest.Conclusion:1,The indices of NE and Ang Ⅱ in the plasma of Adrismycin-inducenephropathy rats were obviously increased which were positively relatedwith the indices morphology and the relative area of interstitial fibrosis.It proved the great activity of sympathetic nerve could damage thekidney and promote tubulointerstitial fibrosis mediates.2,The Moxonidine and Lotensin can all lower urine albumin excretionand the indices NE and Ang Ⅱ in the plasma and alleviate the lesion ofrenal tissue and reduce the deposition of ECM in obstructive kidney anddefer tubulointerstitial fibrosis. The combination of Moxonidine andLotensin was better than Moxonidine or Lotensin alone.3,Moxonidine and Lotensin have the inhibition on the expression ofTGF-β1 in protein and mRNA and the synthesization of ECM inobstructive kidney. They can resolve ECM by adjusting the unbalance ofMMP-1/TIMP-1 in obstructive kidney. The combination of Moxonidineand Lotensin was better than Moxonidine or Lotensin alone.4,Moxonidine and Lotensin can protect the kidney by inhibiting theactivity of sympathetic nerve and down-regulating significantly theexpression of TGF-β1, TIMP-1 et al and inhibiting tubulointerstitialfibrosis.Moxonidine;...