title: Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney.
abstract: Diabetic kidney disease is the leading cause of end-stage renal disease. Genetic factors have been suggested to contribute to its susceptibility. However, results from genetic studies are disappointing possibly because the role of glucose in diabetic kidney disease predisposed by epigenetic mechanisms has not been taken into account. Since thioredoxin-interacting protein (TXNIP) has been shown to play an important role in the pathogenesis of diabetic kidney disease, we tested whether glucose could induce expression of TXNIP in the kidney by epigenetic mechanisms. In kidneys from diabetic Sur1-E1506K(+/+) mice, hyperglycemia-induced Txnip expression was associated with stimulation of activating histone marks H3K9ac, H3K4me3, and H3K4me1, as well as decrease in the repressive histone mark H3K27me3 at the promoter region of the gene. Glucose also coordinated changes in histone marks and TXNIP gene expression in mouse SV40 MES13 mesangial cells and the normal human mesangial cell line NHMC. The involvement of histone acetylation in glucose-stimulated TXNIP expression was confirmed by reversing or enhancing acetylation using the histone acetyltransferase p300 inhibitor C646 or the histone deacetylase inhibitor trichostatin A. Thus, glucose is a potent inducer of histone modifications, which could drive expression of proinflammatory genes and thereby predispose to diabetic kidney disease.
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, Malmö, Sweden. Electronic address: Yang.de_marinis@med.lu.se.
authors.forename: Yang
authors.initials: Y
authors.lastname: De Marinis
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, Malmö, Sweden; Department of Endocrinology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Mengyin
authors.initials: M
authors.lastname: Cai
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, Malmö, Sweden.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bompada
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, Malmö, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Atac
authors.affiliation: Vascular Excitation-Transcription Coupling Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Kotova
authors.affiliation: Clinical Pathology, Department of Translational Medicine, Skåne University Hospital Malmö, Lund University, Malmö, Sweden.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Johansson
authors.affiliation: Vascular Excitation-Transcription Coupling Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Eliana
authors.initials: E
authors.lastname: Garcia-Vaz
authors.affiliation: Vascular Excitation-Transcription Coupling Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, Malmö, Sweden; Finnish Institute for Molecular Medicine, Helsinki University, Helsinki, Finland.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology*; D044127:Epigenesis, Genetic; D042421:Histone Code; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D008822:Mice, Transgenic; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D013879:Thioredoxins
keywords: diabetic kidney disease; histone acetyltransferase (HAT); histone deacetylase (HDAC); histone modification; hyperglycemia; thioredoxin-interacting protein (TXNIP)