The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition

• Published in: Journal of biomedical science Vol. 29; no. 1; pp. 1 - 46
• Main 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
• Format: Journal Article
• Language: English
• Published: Basel BioMed Central Ltd 28.06.2022; BioMed Central; BMC
• Subjects: Acute kidney injury; Adenine; Analysis; Animal models; Antibodies; Apoptosis; Autocrine signalling; Body temperature; Cell cycle; Cell proliferation; Chronic kidney disease; Chronic kidney failure; Down-regulation; Enzymes; Epithelial cells; Epithelium; Fibrosis; Growth factors; Injuries; Ischemia; Kidney diseases; Kidneys; Laboratory animals; Paracrine signalling; Pathogenesis; Protein folding; Protein synthesis; Proteins; Proteomics; Reperfusion; Scientific equipment and supplies industry; Transcription factors; Transforming growth factor-b1; Transforming growth factors; Tumor necrosis factor receptors; Unfolded protein response; XBP1; United States; Taiwan; United States > US
• ISSN: 1423-0127; 1021-7770; 1423-0127
• DOI: 10.1186/s12929-022-00828-9

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 (XBP1 cKO ) 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. XBP1 cKO 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.