title: Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation.
abstract: Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacological agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3 months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases' (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3-lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI-1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes-related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation.
authors.affiliation: Department of Nephrology, Second Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA.
authors.forename: Yangwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA; Cardiovascular Center, First Hospital of Jilin University, Changchun, China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Second Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA.
authors.forename: Manyu
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Nephrology, Second Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Nephrology, Second Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Kong
authors.affiliation: Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA; Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Department of Nephrology, Second Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Cui
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Jingying
authors.initials: J
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Nephrology, Second Hospital of Jilin University, Changchun, China. Electronic address: miaolining55@163.com.
authors.forename: Lining
authors.initials: L
authors.lastname: Miao
authors.affiliation: Kosair Children's Hospital Research Institute and Department of Pediatrics of University of Louisville, Louisville, KY, USA; Department of Radiation Oncology, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. Electronic address: l0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000107:Acetylation; D000818:Animals; D047369:Chromatin Immunoprecipitation; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D006657:Histones / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D006657:Histones; D050880:p300-CBP Transcription Factors; D048670:MAP Kinase Kinase 4; D003474:Curcumin
keywords: Curcumin; Diabetic nephropathy; Fibrosis; Histone acetylation; JNK; p300/CBP