title: The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway.
abstract: The thiazolidinedione pioglitazone, which is also a PPAR-γ agonist, now is widely used in patients with hypercholesterolemia and hypertriglyceridemia. NF-κB is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. The aim of the present study was to evaluate whether the activation of PPAR-γ attenuates the cisplatin-induced NF-κB activation in cisplatin nephrotoxicity. The results showed that the PPAR-γ agonist pioglitazone decreased the expression of NF-κB p65 transcription target genes (e.g., IL-6, IL-1β, and TNF-α) and inhibited histological injury and inflammatory cells infiltration in cisplatin nephrotoxicity. The suppression of NF-κB activity following pioglitazone treatment inhibited the cisplatin-induced IκB-α degredation and NF-κB p65 subunit translocation. Translocation of the NF-κB p65 subunit depends on p65 acetylation, which primarily regulated by SIRT1 or p300. Notably, AMP kinase (AMPK) activation not only decreased the phosphorylation, activation and p65 interaction of p300 but also increased SIRT1 expression, activation and p65 binding, thus leading to a significant reduction in p65 acetylation. Interestingly, the reduction of IL-6, TNF-α and IL-1β, the inhibition of histological injury and the inflammatory cells infiltration following pioglitazone treatment in cisplatin nephrotoxicity were attenuated after treatment with the PPAR-γ antagonist GW9662. These results suggest that the PPAR-γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through a reduction in p65 acetylation via the AMPK-SIRT1/p300 pathway.
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences & Sichuan Provincial People's Hospital, Chengdu, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong Unversity of Science and Technology, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China. Electronic address: jhli@tjh.tjmu.edu.cn.
authors.forename: Junhua
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China. Electronic address: xugang@tjh.tjmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000737:chemistry; D002945:Cisplatin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047495:PPAR gamma; D020011:Protective Agents; C498144:Rela protein, mouse; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002945:Cisplatin; D000077205:Pioglitazone
keywords: Acute kidney injury; Cisplatin; NF-κB p65 acetylation; PPAR-γ