Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney

被引:53
作者
Deb, Dilip K. [1 ]
Bao, Riyue [2 ]
Li, Yan Chun [1 ]
机构
[1] Univ Chicago, Dept Med, 900 E 57th St,KCBD 9110, Chicago, IL 60637 USA
[2] Univ Chicago, Ctr Res Informat, Div Biol Sci, Chicago, IL 60637 USA
基金
美国国家卫生研究院;
关键词
diabetic complication; renal fibrosis; histone acetylation; ChIP-Seq; protein kinase A; VITAMIN-D-RECEPTOR; HISTONE ACETYLATION; GENE-EXPRESSION; MESANGIAL CELLS; GROWTH-FACTOR; HIGH GLUCOSE; TGF-BETA; CHROMATIN; MODEL; TRANSCRIPTION;
D O I
10.1096/fj.201601116R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hyperglycemia is a major pathogenic factor that promotes diabetic nephropathy, but the underlying mechanism remains incompletely understood. Here, we show that high glucose induced cAMP response element-binding protein (CREB)-binding protein (CBP)-mediated H3K9/14 hyperacetylation in approximately 5000 gene promoters in glomerular mesangial cells, including those of Tgfb1, Tgfb3, and Ctgf, the major profibrotic factors that are known to drive diabetic renal fibrogenesis. In these promoters, H3K9/14 hyperacetylation was closely associated with NF-kappa B or CREB motifs. Chromatin immunoprecipitation assays confirmed that hyperglycemia promoted phospho-p65 or phospho-CREB and CBP bindings and RNA polymerase II recruitment to these promoters in mesangial cells as well as in glomeruli that were purified from type I and type II diabetic mice. Under hyperglycemia, cAMP production and PKA activity were markedly increased as a result of glucose transporter 1-mediated glucose influx that drives glucose metabolism and ATP production, which led to increased phosphorylation of p65 and CREB. Inhibition of adenylyl cyclase or PKA activity blocked p65 and CREB phosphorylation, CBP recruitment, and histone acetylation in these promoters. Collectively, these data demonstrate that the cAMP-PKA pathway plays a key role in epigenetic regulation of key profibrotic factors in diabetes.-Deb, D. K., Bao, R., Li, Y. C. Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney.
引用
收藏
页码:2065 / 2075
页数:11
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