HDAC Dependent Transcriptional Repression of Bmp-7 Potentiates TGF-β Mediated Renal Fibrosis in Obstructive Uropathy

作者：Scott R. Manson, Joseph Song, Keith A. Hruska, Paul F. Austin · 发表于：The Journal of Urology · 年份：2013 · DOI：10.1016/j.juro.2013.06.110 · 被引用次数：37 · 研究领域：Chronic Kidney Disease and Diabetes、Acute Kidney Injury Research、TGF-β signaling in diseases

PURPOSE: Recombinant BMP-7 inhibits the pathogenesis of renal injury in response to various stimuli. However, little is known about the molecular regulation of endogenous BMP-7 and its renal protective functions. We examined transcriptional regulation of Bmp-7 and its role in the pathogenesis of renal injury resulting from urinary tract dysfunction. MATERIALS AND METHODS: Obstruction induced renal injury was modeled in vivo in mice by unilateral ureteral obstruction and in vitro in primary kidney cells by treatment with transforming growth factor-β, a profibrotic cytokine that is increased in the obstructed kidney. RESULTS: Unilateral ureteral obstruction resulted in the loss of BMP-7 expression in conjunction with histone deacetylation and transcriptional repression of the Bmp-7 promoter. The histone deacetylase inhibitor trichostatin A stimulated Bmp-7 expression in primary kidney cells. Trichostatin A also inhibited the expression of transforming growth factor-β dependent profibrotic genes in a manner that depended on BMP receptor signaling. These findings extended to the obstructed kidney in vivo, in which trichostatin A treatment restored the expression of Bmp-7 along with BMP-7 mediated suppression of transforming growth factor-β dependent signaling pathways. Finally, trichostatin A stimulated activation of the BMP-7 pathway the ameliorated obstruction induced renal injury by preventing disruption of the renal architecture and the development of renal fibrosis. CONCLUSI...