Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney.
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 ofTgfb1, Tgfb3, andCtgf, the major profibrotic factors that are known to drive diabetic renal fibrogenesis. In these promoters, H3K9/14 hyperacetylation was closely associated with NF-κB 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.
Department of Medicine The University of Chicago, Chicago, Illinois, USA.
Dilip K
DK
Deb
Center for Research Informatics, Division of Biological Sciences, The University of Chicago, Chicago, Illinois, USA.
Riyue
R
Bao
Department of Medicine The University of Chicago, Chicago, Illinois, USA; cyan@medicine.bsd.uchicago.edu.
Yan Chun
YC
Li
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D006943:Hyperglycemia / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction
D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D009687:Nuclear Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
ChIP-Seq; diabetic complication; histone acetylation; protein kinase A; renal fibrosis