Effect Of Quercetin On Tubulointerstitial Fibrosis In Rat Model Of Chronic Cyclosporine A Nephrotoxicity

Objective:To observe the effect of quercetin on tubulointerstitial fibrosis,and investigate a possible mechanism in rat models of chronic cyclosporine A(CsA) nephrotoxicity.Methods:Before being entered in the study protocol,male SD rats fed a low-sodium diet for 1 week,were then divided randomly into four groups as follows:①normal control group(low-sodium diet),②CsA model group(intragastric administration with CsA was dissolved in olive oil 25mg.kg^-1.d^-1),③quercetin treatment group (intragastric administration with CsA dissolved in olive oil 25mg.kg^-1.d^-1 and quercetin 15 mg.kg^-1.d^-1),④vehicle control group(intragastric administration with olive oil 2.5 ml.kg^-1.d^-1).These rats were sacrificed at 4,6 weeks.Their body weight, serum creatinine,and urinary protein were measured respectively,the morphological changes of renal tissue were evaluated by hematoxylin-eosin(HE) and Masson stain, the expression of transforming growth-β1(TGF-β1),collagen-Ⅳ(COL-Ⅳ),α-sooth muscle actin(α-SMA),and osteopontin(OPN) in renal tissue were respectively detected by immunchistachemistry methods or Real Time-PCR.Results:①Decreased body weight,increased serum creatinine and urinary protein were found in CsA model and quercetin treatment groups(P＜0.05),but changes of these parameters in quercetin treatment group were alleviated compared with CsA model group(P＜0.05)②Tubulointerstitial injury with interstitial fibrosis and tubular atrophy in quercetin treatment guoup was decreased compared with CsA model guoup.③The levels of TGF-β1,COL-Ⅳ,α-SMA,and OPN in both of CsA model and quercetin treatment groups were increased remarkably compared with normal control or vehicle control group(P＜0.01),while compared to CsA model group,aforesaid parameters were significantly reduced in quecetine treatment(P＜0.01).④Compared to normal control or vehicle control group,the expression of TGF-β1,Smad2/3,and Smad7 mRNA in the renal tissue were markedky upregulated in CsA model and quercetin treatment groups(P＜0.05),the former were higher than the latter(P＜0.05), while the expression of Smad7mRNA at the sixth week was higher than the former (P＜0.01)⑤There were no significant difference in aforesaid parameters between the normal control group with the vehicle control group throughout experimental period.⑥The score of tubulointerstitial fibrosis was positively correlated with the TGF-β1, COL-Ⅳ,α-SMA,and OPN,respectively.Conclusions:①Quercetin may attenuate the chronic nephrotoxicity of CsA through. decreased urinary protein,downregulated TGF-β1,OPN,α-SMA,and COL-Ⅳexpression,and delayed progression of CsA-induced tubulointerstitial fibrosis.②Suppression of the tubulointerstitial fibrosis by quercetin may be associated with the activation of TGF-β1/Smad7 signaling pathway.