Protection of rosiglitazone against renal interstitial lesion and its mechanism

Abstract

To investigate the protection of rosiglitazone (RSG) against renal interstitial lesion and its mechanism. Male adult SD rats were randomly divided into 5 groups: Sham group, undergoing sham operation; Sham + RSG group, undergoing sham operation and treated with RSG (30 mg.kg(-1).d(-1)); UUO group, undergoing unilateral left ureter obstruction; UUO + RSG5 group, undergoing UUO and treated with RSG (5 mg.kg(-1).d(-1)); and UUO + RSG30 group, undergoing UUO and treated with RSG (30 mg.kg(-1).d(-1)). Except the Sham group, the other groups were divided into 3 subgroups of 6 approximately 8 rats to be killed 3, 7, and 14 days after the intervention and their left kidneys were taken out to undergo light microscopy by Masson staining to observe the renal interstitial fibrosis index and to undergo immunohistochemistry with mice anti-rat ED-1 antibody to calculate the ED-1 (specific marker antigen on the surface of monocyte/macrophage) positive cells. Homogenate of renal cortex was made. ELISA was used to detect the protein expression of transforming growth factor beta(1) (TGF-beta(1)), bone morphogenetic protein (BMP)-7, and PAI-1 gene. RT-PCR was used to detect the mRNA expression of BMP-7 and TGF-beta(1) downstream effector genes: CTGF and Smad6. Fourteen days after the intervention, the fibrosis index of the UUO group were significantly increased and the fibrosis index values of both UUO + RSG5 and UUO + RSG30 groups were significantly lower than that of the UUO group (both P = 0.000) with a significant difference between the 2 UUO + RSG groups. Three days after the intervention, the number of ED-1 positive cell began to increase in the UUO group and peaked 7 days after, however, the number of ED-1 positive cells of the 2 UUO + RSG groups were significantly lower than that of the UUO group. TGF-beta(1) mRNA and protein were highly expressed in the UUO group, however, the expression of TGF-beta(1) mRNA in the 2 UUO + RSG groups was significantly lower, especially in the UUO + RSG30 group, in comparison with the UUO group (both P < 0.05). The CTGF mRNA expression was increased time-dependently in the UUO group, however the CTGF mRNA expression of the 2 UUO + RGS groups was significantly inhibited dose- and time-dependently (all P < 0.05). In comparison with that in the Sham group, the Smad6 mRNA expression was significantly increased in the Sham + RSG group (P < 0.05), and was decreased time-dependently in the UUO group; however, the decrease of Smad6 mRNA expression was significantly reversed in the 2 UUO + RSG groups, especially in the UUO + RSG30 group (P < 0.05). The expression of BMP-7 protein and mRNA was significantly lower in the UUO group time-dependently. However, the BMP-7 mRNA expression of the 2 UUO + RSG group, especially of the UUO + RSG30 group, was significantly higher than that of the UUO group (both P < 0.05). The PAI-1 protein expression of the UUO group was significantly higher 7 and 14 days after (both P < 0.05), however, the PAI-1 protein expression of the 2 UUO + RSG groups was significantly lower than that of the UUO group (both P < 0.05). RSG inhibits the renal interstitial macrophage infiltration, downregulates the expression of the down-stream target genes, and up-regulate the BMP-7 expression, thus blocking the renal fibrosis.