| Organ transplantation acquired great curative effect to treat the end stage disease,Cyclosporine A(CsA) has become the cornerstone of clinical immuno suppression.In essence,it predominantly improves the short-term survival of organ transplantation.CsA is the first-line drugs for the treatment of rejection after transplantation,although numerous new ones come into view.Nevertheless,CsA therapy has strong drawbacks,especially nephrotoxity.Bypast Researches show that CsA injure kidney by affecting RAS,transforming growth factor-β1(TGF-β1) and peroxisome proliferator-activated receptorγ(PPARγ).Pathologic show endarterium fibrosis,glomerulus sclerosis,tubule atrophy and Interstitial fibrosis.Fibrosis of kidney induced by CsA has been an urgent problem-in-discussing of the development of transplantation.Rosiglizone(RGZ),a member of thiazolidinediones(TZDs),not only is believed involving in the cellular metabolism,but also plays an important role on ameliorating inflammation and fibrosis.We establish the renal fibrosis model resulted from CsA at the basis of low salt diet(LSD),observe the protective effects of RGZ on the nephrotoxity induced by CsA.Methods1.Healthy male SD rats fed with LSD one week later were randomly assigned to normal group,rosiglitazone(5mg.kg-1.d-1) group,cyclosporine A(15mg.kg-1.d-1) group,rosiglitazone treatment(15mg.kg-1.d-1+5mg.kg-1.d-1) group after CCN.3 rats of each group were sacrificed randomly 2 weeks later,the rest were sacrificed at the end of the experiment(5 weeks later).2.General conditions and biochemistic investigation,Body weight was measured at the onset and the end of the experiment.Urinary creatine,serum creatine and albumin were investigated.3.Histology,Interstitial mononuclear cells was counted in HE staining,and interstitial fibrosis was calculated in Masson's staining.4.Immunohistochemistry(IHC),CollagenⅣ(ColⅣ) and CD68 were stained with SP kit.5.The mRNA expression of matrix metalloproteinase-9(MMP-9) and tissue inhibitor of matrix metalloproteinase-1(TIMP-1)were detected with Reverse tra nscriptio n-polymerase chain reaction(RT-RCR).Results1.Body weight,There is markedly decrease of body weight in CsA-treated rats compared with that of control group,(P＜0.05).RGZ reduces the decrease of body weight compared with that in CsA-treated rats,but not significant at the same time-point(p＞0.05).compared with the control group,there is no difference in RGZ group(p＞0.05).2.Biochemistry,Ccr of CsA-treated group decreases significantly(p＜0.05),and RGZ ameliorates the decrease of Ccr markedly at 5 weeks(p＜0.05).The serum level of ALB decreasea markedly in CsA-treated group(p＜0.05),however,RGZ failes to improve the ALB either at 2 weeks or at 5weeks(p＞0.05).compared with the control group,there is no difference in RGZ group(p＞0.05).3.Interstitial mononuclear cells infiltration,The amount of interstitial mononuclear cells infiltrated with HE staining increase markedlyin CsA-treated group at 2 weeks(p＜0.05),RGZ ameliorate the increase of interstitial mononuclear cells significantly at 2 weeks(p＜0.05).The IHC staining of CD68 increases markedly in CsA-treated group compared with that of control group both 2 weeks and 5 weeks(P＜0.05).RGZ significantly reduces the IHC staining of CD68(P＜0.05). compared with the control group,there is no difference in RGZ group(p＞0.05).4.Interstitial fibrosis,Interstitial fibrosis detected with Masson's staining in CsA-treated group progressed with time,and peeks at 5 weeks.RGZ significantly alleviates fibrosis at 5 weeks(p＜0.05).The IHC staining of ColⅣincreases markedly in CsA-treated group compared with that of control group both at 2 weeks and at 5 weeks(P＜0.05).RGZ significantly reduces the IHC staining of ColⅣ(P＜0.05).compared with the control group,there is no difference in RGZ group(p＞0.05).5.RT-PCR detecting mRNA expression of MMP-9,The level of MMP-9 increases markedly at 2 weeks and at 5 weeks(P＜0.05),and peeked at 2 weeks in CsA-treated group.This proneness is ameliorated by RGZ significantly at the two time-points(P＜0.05).compared with the control group,there is no difference in RGZ group(p＞0.05).6.RT-PCR detecting mRNA expression of TIMP-1,The level of TIMP-1 increased markedly at 2 weeks and at 5 weeks(P＜0.05),and peeked at 5 weeks in CsA-treated group.This proneness is ameliorated by RGZ significantly at the two time-points(P＜0.05).compared with the control group,there is no difference in RGZ group(p＞0.05).Conclusions1.RGZ ameliorates the progression of renal interstitial fibrosis induced by CsA through inhibites the infiltration of mononuclear cell and inflammation reaction.2.Rosiglitazone may inhibite renal interstitial fibrosis and slow the progression of renal function by regulating expression of MMP-9,TIMP-1. |
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