Increased susceptibility to acute kidney injury due to endoplasmic reticulum stress in mice lacking tumor necrosis factor-α and its receptor 1

Lianghu Huang, Ruihua Zhang, Jin Wu, Jian Chen, Fabrizio Grosjean, Lisa H. Satlin, Janet D. Klein, Jeffrey M. Sands, Gary E. Striker, Jianming Tan, Feng Zheng

Research output: Contribution to journalArticle

Abstract

Endoplasmic reticulum (ER) stress is actively involved in acute organ injury. Since tumor necrosis factor α (TNFα) plays a role in acute kidney injury, and induces ER stress and cell death in vitro, we examined the contribution of TNFα to acute kidney ER stress induced by tunicamycin. Contrary to expectation, tunicamycin caused much more severe kidney injury in TNFα/ than in wild-type mice. The major site of kidney injury in TNFα/ mice was proximal tubules, which showed extensive cell vacuolation, lipid accumulation, and apoptosis. Reconstitution of TNFα/ mice with TNFα 24 h before tunicamycin injection reversed the susceptibility. When TNFα-receptor-deficient mice were treated with tunicamycin, severe renal injury developed in TNFR1/ but not TNFR2/ mice, suggesting this aspect of TNFα action was through TNF receptor-1 (TNFR1). In response to tunicamycin-induced acute ER stress, kidneys from neither TNFα/ nor TNFR1/ mice showed a significant increase in phosphorylated eukaryotic translation initiation factor 2α (eIF2α), a key step in ER stress regulation. Moreover, proximal tubular cells from TNFR1/ mice did not show increased eIF2α phosphorylation in response to tunicamycin and were susceptible to ER stress-induced cell death. Finally, treatment of proximal tubule cells isolated from TNFR1/ mice with an inhibitor of eIF2α phosphatase increased the levels of phosphorylated eIF2α and substantially reduced tunicamycin-induced cell death. Thus, disruption of TNFR1 signaling leads to dysregulation of eIF2α and increased susceptibility to acute ER stress injury in the kidney.

Original languageEnglish
Pages (from-to)613-623
Number of pages11
JournalKidney International
Volume79
Issue number6
DOIs
Publication statusPublished - Mar 2011

Keywords

  • acute kidney injury
  • proximal tubular cells
  • tumor necrosis factor-α

ASJC Scopus subject areas

  • Nephrology

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    Huang, L., Zhang, R., Wu, J., Chen, J., Grosjean, F., Satlin, L. H., Klein, J. D., Sands, J. M., Striker, G. E., Tan, J., & Zheng, F. (2011). Increased susceptibility to acute kidney injury due to endoplasmic reticulum stress in mice lacking tumor necrosis factor-α and its receptor 1. Kidney International, 79(6), 613-623. https://doi.org/10.1038/ki.2010.469