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

Am J Physiol Cell Physiol. 2015 Apr 15;308(8):C621-30. doi: 10.1152/ajpcell.00096.2014. Epub 2015 Jan 7.


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.

Keywords: activating transcription factor 4; advanced glycation end products; endoplasmic reticulum stress; p16; premature senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / 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 Tubules / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering


  • ATF4 protein, human
  • CDKN2A protein, human
  • Cadherins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Glycation End Products, Advanced
  • Heat-Shock Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Activating Transcription Factor 4
  • molecular chaperone GRP78