We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition.
- Authors
Chen, Jia-Huang; Wu, Chia-Hsien; Jheng, Jia-Rong; Chao, Chia-Ter; Huang, Jenq-Wen; Hung, Kuan-Yu; Liu, Shing-Hwa; Chiang, Chih-Kang
- Abstract
Background: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Methods: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia–reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. Results: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-β1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. Conclusion: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.
- Subjects
UNFOLDED protein response; CHRONIC kidney failure; ACUTE kidney failure; RENAL fibrosis; KIDNEY diseases; KIDNEY injuries; URETERIC obstruction
- Publication
Journal of Biomedical Science, 2022, Vol 29, Issue 1, p1
- ISSN
1021-7770
- Publication type
Article
- DOI
10.1186/s12929-022-00828-9