| First Author | Huang L | Year | 2011 |
| Journal | Kidney Int | Volume | 79 |
| Issue | 6 | Pages | 613-23 |
| PubMed ID | 21150875 | Mgi Jnum | J:186880 |
| Mgi Id | MGI:5433456 | Doi | 10.1038/ki.2010.469 |
| Citation | Huang L, et al. (2011) Increased susceptibility to acute kidney injury due to endoplasmic reticulum stress in mice lacking tumor necrosis factor-alpha and its receptor 1. Kidney Int 79(6):613-23 |
| abstractText | Endoplasmic reticulum (ER) stress is actively involved in acute organ injury. Since tumor necrosis factor alpha (TNFalpha) plays a role in acute kidney injury, and induces ER stress and cell death in vitro, we examined the contribution of TNFalpha to acute kidney ER stress induced by tunicamycin. Contrary to expectation, tunicamycin caused much more severe kidney injury in TNFalpha-/- than in wild-type mice. The major site of kidney injury in TNFalpha-/- mice was proximal tubules, which showed extensive cell vacuolation, lipid accumulation, and apoptosis. Reconstitution of TNFalpha-/- mice with TNFalpha 24 h before tunicamycin injection reversed the susceptibility. When TNFalpha-receptor-deficient mice were treated with tunicamycin, severe renal injury developed in TNFR1-/- but not TNFR2-/- mice, suggesting this aspect of TNFalpha action was through TNF receptor-1 (TNFR1). In response to tunicamycin-induced acute ER stress, kidneys from neither TNFalpha-/- nor TNFR1-/- mice showed a significant increase in phosphorylated eukaryotic translation initiation factor 2alpha (eIF2alpha), a key step in ER stress regulation. Moreover, proximal tubular cells from TNFR1-/- mice did not show increased eIF2alpha 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 eIF2alpha phosphatase increased the levels of phosphorylated eIF2alpha and substantially reduced tunicamycin-induced cell death. Thus, disruption of TNFR1 signaling leads to dysregulation of eIF2alpha and increased susceptibility to acute ER stress injury in the kidney. |
