Simvastatin ameliorates renal fibrosis via suppressing uterine sensitization‐associated gene‐1 (USAG‐1), a BMP‐7 antagonist, in mouse adenine‐induced tubulointerstitial injury model

Abstract

Background & PurposeIt is known that BMP‐7 counteracts with TGF‐β, the dominant molecule promoting renal fibrosis, and that uterine sensitization‐associated gene‐1(USAG‐1), the dominant BMP‐7 antagonist expressing in distal tubular epithelial cells, promotes renal fibrosis. In this study, we investigated whether simvastatin (SIM), one of the HMG‐CoA reductase inhibitors, attenuates renal fibrosis by modulating BMP‐7 and USAG‐1 mediated pathway.Method & ResultsC57/BL6 mice fed by 0.2% adenine‐containing diet for 4 weeks showed significant increase of blood urea nitrogen (BUN) accompanied with severe tubulointerstitial fibrosis. SIM treatment for two weeks (50mg/kg/day) significantly reduced BUN compared with the control group (p<0.01). In pathological analysis, the area of fibrosis and the expression of alpha smooth muscle actin were significantly attenuated by SIM (p<0.05). In quantitative real‐time PCR, USGA‐1 expression was significantly lower in the SIM group (p<0.05). MDCK cells (distal epithelial tubular cells) incubated with TGF‐β (5ng/ml) for 72 hours showed increased expression of USAG‐1. SIM significantly reduced USAG‐1 expression (p<0.01). Several database analyses predicted the binding sites of HOXA‐13, a transcriptional factor, in the promoter region of USAG‐1 gene. The expression assay in vitro suggested that HOXA13 functions as a suppressor of the USAG‐1 gene and SIM decreased USAG‐1 expression by enhancing HOXA13.ConclusionOur data showed that SIM ameliorated renal fibrosis by suppressing USAG‐1. Decreased USAG‐1 levels may enhance the counteract effect of BMP‐7 against TGF‐β. We also demonstrated that HOXA13 plays a crucial role in the mechanism of this action by SIM.