title: Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy.
abstract: Premature senescence is an important event during diabetic nephropathy (DN) progression. Here, we investigated the role of endoplasmic reticulum (ER) stress-regulated activation of transcription factor 4 (ATF4)/p16 signaling in the premature senescence of renal tubular epithelial cells (RTECs) during DN development. In the renal tissues of Type 2 DN patients, we detected an increased number of senescent cells; elevated deposition of advanced glycation end products (AGEs); upregulated expression of ER stress marker, glucose-regulated protein 78; as well as overexpression of ATF4 and p16. Similarly, these phenomena were also observed in cultured mouse RTECs following AGE treatment. Interestingly, AGE-induced p16 expression and premature senescence were successfully attenuated by ER stress inhibitor and ATF4 gene silencing. Moreover, AGE-induced premature senescence was mimicked by ER stress inducers and ATF4 overexpression, while suppressed by p16 gene silencing. In addition, ER stress inducers can augment ATF4 expression. Therefore, our results demonstrate that the ER stress-regulated ATF4/p16 pathway is involved in the premature senescence of RTECs during DN progression.
authors.affiliation: Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China; and State Key Laboratory of Kidney Disease, Kidney Center of the People's Liberation Army, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China; and.
authors.forename: Ju-Rong
authors.initials: JR
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Kidney Disease, Kidney Center of the People's Liberation Army, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing, China.
authors.forename: Xiang-Mei
authors.initials: XM
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Kidney Disease, Kidney Center of the People's Liberation Army, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing, China.
authors.forename: Guang-Yan
authors.initials: GY
authors.lastname: Cai
authors.affiliation: Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China; and.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Lin
authors.affiliation: Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China; and heynmail@163.com.
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: He
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D019588:Aging, Premature / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C497109:ATF4 protein, human; C000614131:CDKN2A protein, human; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000091342:Endoplasmic Reticulum Chaperone BiP; D017127:Glycation End Products, Advanced; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4
keywords: activating transcription factor 4; advanced glycation end products; endoplasmic reticulum stress; p16; premature senescence