- 作者: Jia-Huang Chen, Chia-Hsien Wu, Jia-Rong Jheng, Chia-Ter Chao, Jenq-Wen Huang, Kuan-Yu Hung, Shing-Hwa Liu & Chih-Kang Chiang
- 作者服務機構: 1.Center for Biotechnology, National Taiwan University, Taipei, Taiwan 2.Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan 3.Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan 4.Graduate Institute of Toxicology, College of Medicine, National Taiwan University, No.1 Jen Ai road section 1, Taipei, 100, Taiwan
- 中文摘要:
- 英文摘要:
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 diferent 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 infuences 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 fbrosis. XBP1cKO mice exhibited more severe renal fbrosis 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 identifed TNF receptor associated protein 1 (Trap1)
as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing
XBP1 induced profbrotic factor expressions and cell cycle arrest.
Conclusion: The loss of XBP1 in kidney injury was profbrotic, and the process was mediated by autocrine and
paracrine regulations in combination. The present study identifed the XBP1-Trap1 axis as an instrumental mechanism
responsible for post-AKI fbrosis, which is a novel regulatory pathway. - 中文關鍵字:
- 英文關鍵字: Unfolded protein response, XBP1, Fibrosis, Acute kidney injury, Chronic kidney disease