Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy

• Published in: American Journal of Physiology: Cell Physiology 2015-04, Vol.308 (8), p.C621-C630
• Main Authors: Liu, Jun, Yang, Ju-Rong, Chen, Xiang-Mei, Cai, Guang-Yan, Lin, Li-Rong, He, Ya-Ni
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - biosynthesis; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Aged; Aging, Premature - metabolism; Animals; Cadherins - biosynthesis; Cells, Cultured; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Endoplasmic reticulum; Endoplasmic Reticulum - pathology; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Epithelial Cells - cytology; Female; Glycation End Products, Advanced - metabolism; Heat-Shock Proteins - biosynthesis; Humans; Kidney diseases; Kidney Tubules - cytology; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nephrology; Oxidative stress; Protein expression; RNA Interference; RNA, Small Interfering; Senescence; Stress response
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00096.2014

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.