Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Wang, Yangwei^1,2,3  Wang, Yonggang^2,3,4  Luo, Manyu^1,2,3  Wu, Hao^1,2,3  Kong, Lili^1,2,3  Xin, Ying^2,3,5  Cui, Wenpeng^1,2,3  Zhao, Yunjie⁶  Wang, Jingying⁶  Liang, Guang⁶  Miao, Lining¹  Cai, Lu^2,3,7,8 

[1] Jilin Univ, Hosp 2, Dept Nephrol, Changchun 130041, Peoples R China

[2] Univ Louisville, Kosair Childrens Hosp, Res Inst, Louisville, KY 40292 USA

[3] Univ Louisville, Dept Pediat, Louisville, KY 40292 USA

[4] Jilin Univ, Hosp 1, Cardiovasc Ctr, Changchun 130041, Peoples R China

[5] Jilin Univ, Key Lab Pathobiol, Minist Educ, Changchun 130041, Peoples R China

[6] Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou, Peoples R China

[7] Univ Louisville, Dept Radiat Oncol, Louisville, KY 40292 USA

[8] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY USA

关键词: Diabetic nephropathy;    Fibrosis;    JNK;    p300/CBP;    Histone acetylation;    Curcumin;   

DOI  :  10.1016/j.bbadis.2014.11.006

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier B.V. All rights reserved.

【 授权许可】

Free