The Effects Of Rosiglitazone On The Experimental Tubulointerstitial Fibrosis Of Rats

OBJECTIVE : The tubulointerstitial fibrosis(TIF) and progressive deterioration of the renal impairment are almost the common pathway by which all the kidney diseases progress to end stage renal failure.Tubular epithelial-myofibroblast transdifferentiation (TEMT) may play an important role in the pathogenesis of renal interstitilial fibrosis which many factors involve. Many studies showed that CTGF, a downstream factor of TGF-β1, can increase the synthesis of external cell matrix(ECM). Thiazolidinedione rosiglitazone is an insulin-sensitizing agent. The Studies suggested that thiazolidinediones can amelioration diabetic glomerular sclerosis .The recent study shows that bone morphogenetic protein-7(BMP-7) may promote maintenance of epithelial phenotypein in vitro.This study will investigate the expression of CTGF, BMP-7, CD68, α -smooth muscle actin( α -SMA), FN, TIMP-1, MMP-3 in UUO rats and the effects of rosiglitazone treatment on TIF.We will illuminate whether rosiglitazone exerted a role to block TEMT in vivo.We intend to provide a new method and academic foundation for blocking TIEMETHOD: Male wistar rats were randomly subdivided into unilateral ureteral obstruction model group(UUO), large dose rosiglitazone-treatedgroup(LDR), small dose rosiglitazone -treated(SDR), ACEI-treated group and sham-operated group(SOR). From the first day after initial UUO,LDR, SDR and ACEI groups were administrated daily by intragastric administration(ia) respectively at rosiglitazone 8mg/kg, rosiglitazone 4mg/kg , fosinopril lOmg/kg and every day thereafter. UUO and SOR groups were administrated identical voluminal normal saline by ia. At 14, 21, 28 > 42 days after UUO ,4 rats selected randomly from each group were killed .The levels of serum creatinn^ blood cell differential counts ^ blood-fasting sugar(BFS)> glutamate-pyruvate transaminase (GLT) -. 24-hour urine protein were measured at each time point . The degree of tubulointerstitial damage was scored.The protein expression of CTGF, BMP-7 > CI-SIV^ CD68 ^fibronection(FN)> TIMP1 *. MMP3 were detected by immunohistochemitry at each time point.The localization and expression of CTGF and BMP-7 mRNA were detected by hybridization in situ.RESULTS:?The level of serum creatinine was higher significantly in UUO group than that in other groups at day 14,21,28 and 42 (/K0.05) . ?There were no significant difference in the level of 24-hour urine protein BFS and GLT among the five groups(,p > 0. 05). Neutrophil count and categorization increased conspicuously in UUO group than that in other groups (p<0.01) . (3)The number of a-SMA-positive interstitial cells was increased and some tubular epithelial cells also expressed a -SMA at day 14-42 after UUO.? Renal BMP-7 mRNA and BMP-7 protein levels were decreased progressively during the progression of obstructive nephropathy.Compared with the UUO groups,the levels of BMP-7 mRNA and protein were increased significantly in LDR ? SDR and ACEI groups (p<0.01) . ?The expressionlevels of (HX2n a-SMA, FN, TIMP1 in UUO were higher than that in other groups (/K0.05 ) .On the contrary, the expression levels of MMP-3 in UUO were lower than that in other groups. ?The expression levels of CTGF> a-SMA> FN> TIMPK MMP-3 in LDR and SDR were parallel to AECI group.CONCLUSION: UUO is a ripe, well-characterized model of experimental renal disease culminating in tubulointerstitial fibrosis and TEMT. The loss of BMP-7 and increase of CTGF were correlated with the increased expression of a-SMA and the degree of interstitial lesions in obstructive nephropathy .This suggested that BMP-7 may block morphologic transformation of tubular epithelial cells, while CTGF may induce TEMT. Rosiglitazone may suppress fibrosis, at least in part via down-regulating CTGF expression and up-regulating BMP-7 expression in the affected kidney. Rosiglitazone can also extenuate renal inflammation and desrease accumulation of extracellular matrix . Rosiglitazone may extenuate tubulointerstitial fibrosis by combinating with the ligand of PPAR-r^ inhibiting TEMT-. decreasing inflammation and accumulation of ECM. Rosiglitazone is safe and effective. It has no marked adverse effect on hepatic function and BFS. This study showed RSG has a remarkable ability to block the epithelial to myofibroblast transition in vivo.Hepatic function was unaffected in LDR and SDR groups.