| First Author | Zhang J | Year | 2021 |
| Journal | Cell Death Discov | Volume | 7 |
| Issue | 1 | Pages | 44 |
| PubMed ID | 33654072 | Mgi Jnum | J:308364 |
| Mgi Id | MGI:6724605 | Doi | 10.1038/s41420-021-00425-z |
| Citation | Zhang J, et al. (2021) Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation. Cell Death Discov 7(1):44 |
| abstractText | Ischemia-reperfusion (IR) injury to the renal epithelia is associated with endoplasmic reticulum stress (ERS) and mitochondria dysfunction, which lead to oxidative stress-induced acute kidney injury (AKI). X-box binding protein 1 (XBP1), an ERS response protein, could play a prominent role in IR-induced AKI. In this study, we revealed that XBP1 and its downstream target HRD1 participated in the crosstalk between ERS and mitochondrial dysfunction via regulation of NRF2/HO-1-mediated reactive oxidative stress (ROS) signaling. Mice with reduced expression of XBP1 (heterozygous Xbp1+/-) were resistant to IR-induced AKI due to the enhanced expression of NRF2/HO-1 and diminished ROS in the kidney. Downregulation of XBP1 in renal epithelial cells resulted in reduced HRD1 expression and increased NRF2/HO-1 function, accompanied with enhanced antioxidant response. Furthermore, HRD1 served as an E3-ligase to facilitate the downregulation of NRF2 through ubiquitination-degradation pathway, and the QSLVPDI motif on NRF2 constituted an active site for its interaction with HRD1. Thus, our findings unveil an important physiological role for XBP1/HRD1 in modulating the antioxidant function of NRF2/HO-1 in the kidney under stress conditions. Molecular therapeutic approaches that target XBP1-HRD1-NRF2 pathway may represent potential effective means to treat renal IR injury. |
