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

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) 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 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.