Effect of all-trans retinoic acid on liver fibrosis induced by common bile duct ligation in rats

Abstract

The aim of this study was to investigate the effect and possible mechanism of all-trans retinoic acid (ATRA) on liver fibrosis induced by common bile duct ligation (CBDL) in rats. Fifty-three female Wistar rats were randomly divided into 5 groups: sham operation group (group J, 5 animals) and groups A, B, C and D (12 animals in each group). The rats in groups A, B, C and D were subjected to CBDL to induce liver fibrosis, while those in group J to sham operation. From the 3rd week the rats in groups B, C and D respectively received daily administration of ATRA via gastric tube at three different doses [0.1, 1.5 and 7.5 mg/kg body weight (BW)]. Animals were sacrificed at 6th week. Rats' liver tissues were observed for pathologic changes under a light microscope. The protein levels of type I collagen (COL I), matrix metalloproteinase-2 (MMP2), MMP13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) in liver tissues were determined by immunohistochemical techniques. The expression levels of TGF-beta1 and CTGF mRNA in liver tissues were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that loss of normal hepatic architecture and formation of obvious fibrosis were observed in group A, while ATRA treatment for 4 weeks notably alleviated the pathological changes of hepatocytes. The expression of COL I and TIMP-1 proteins in group A was increased, while decreased in ATRA-treated CBDL groups (P<0.05). ATRA (1.5 and 7.5 mg/kg BW) reduced the expression levels of COL I protein more greatly than that of 0.1 mg/kg BW (P<0.05). ATRA treatment increased the protein levels of MMP2 and MMP13. The expression levels of TGF-beta1 and CTGF mRNA in group A were increased. In comparison with group A, the mRNA levels of TGF-beta1 and CTGF in ATRA-treated CBDL groups were significantly decreased (P<0.05). It was concluded that ATRA could inhibit CBDL-induced liver fibrosis in rats by suppressing the expression of TGF-beta1 and CTGF so as to diminish the inhibition of TIMP-1 on MMP2 and MMP13 and increase the activity of MMP2 and MMP13.

Retinoid and TGF-β Families: Crosstalk in Development, Neoplasia, Immunity, and Tissue Repair

“…ATRA inhibits TGF-β stimulation of pro-fibrotic molecules in cultured mesangial cells, including fibronectin and PAI-1 86 . Similarly, ATRA inhibits TGF-β-driven liver fibrosis in a rat common bile duct ligation model 87 . TGF-β increases vascular endothelial growth factor (VEGF) production by cultured smooth muscle cells 88 and endometrial cells; in the latter cells, this effect requires ATRA, which initiates a process whereby VEGF mRNA transcripts are directed toward larger, poly-ribosomes that are more translationally active 89 .…”

All-trans retinoic acid mitigates methotrexate-induced liver injury in rats; relevance of retinoic acid signaling pathway

“…Animals were randomly divided into five groups/six rats each: control saline group: rats were injected with saline (0.2 ml/100 g.bw, I.P) once daily for 10 days; control DMSO group: rats were injected with DMSO, the vehicle of all-trans retinoic acid (ATRA), (0.2 ml /200 g.bw/day, I.P) for 10 consecutive days. MTX group: rats were injected with MTX in a single dose of 20 mg/kg on the sixth day of the experiment; ATRA group: rats were injected with ATRA (7.5 mg/kg/day, I.P) for 10 consecutive days (Rao et al 2010;Wang et al 2008); ATRA/MTX group: rats were injected with ATRA (7.5 mg/kg/day, IP) for 10 consecutive days while a single dose of MTX (20 mg/kg) was injected on the sixth day of ATRA injection. On the 11th day, rats were anesthetized with diethyl ether and blood samples were collected for measurement of blood chemistry.…”

The Controversial Role of Retinoic Acid in Fibrotic Diseases: Analysis of Involved Signaling Pathways

“…Equally, Yang KL et al [16] reported that a RA derivative isolated from the mycelium of Phellinus linteus could antagonize ECM accumulation and liver fibrosis in BALB/c mice by down-regulating reactive oxygen species (ROS) generation and calcium influx, thereby directly affecting transforming growth factor-β1 (TGF-β1). Wang H and co-workers [17] showed that ATRA (1.5 and 7.5 mg/kg) was able to inhibit common bile duct ligation (CBDL)-induced liver fibrosis in female Wistar rats, and ATRA reduced the expression of collagen I protein more greatly than that of 0.1 mg/kg. The expression of type I collagen (COL-I), tissue inhibitors of metalloproteinase-1 (TIMP-1), TGF-β1, and connective tissue growth factor (CTGF) were reduced, whilst He H et al [18] reported that 5 mg/kg ATRA significantly reduced liver fibrosis and nearly eliminated liver necrosis after CBDL in male Sprague-Dawley rats, especially in combination with ursodeoxycholic acid (UDCA).…”