Abstract: FR-PO0379
Targeted Intervention for DcR2 Alleviates AKI by Modulating Tubular Senescence
Session Information
- AKI: Mechanisms - Metabolism and Repair
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Chen, Jia, Army Medical University, Chongqing, China
- Yang, Xin, Army Medical University, Chongqing, China
- Chen, Kehong, Army Medical University, Chongqing, China
- He, Yani, Army Medical University, Chongqing, China
Background
Acute kidney injury (AKI) is a life-threatening condition with high morbidity and mortality. Despite substantial progress in understanding the mechanism of AKI, no effective therapies are available for treatment. We previously found DcR2 is highly expressed in senescent renal tubular cells in patients with AKI and is associated with poor renal prognosis, suggesting targeted DcR2 intervention as a potential treatment.
Methods
We generated DcR2-GFP transgenic and proximal tubular epithelial cell (PTEC)-specific DcR2 conditional knockout (DcR2-CKO) mice. Moderate and severe ischemia-reperfusion (IR) models were employed to assess DcR2's role in AKI. Four-dimensional quantitative proteomics and bioinformatics were utilized to elucidate mechanisms. Antagonistic peptides against DcR2 (AP-D) were screened via phage display and validated in vivo and in vitro.
Results
DcR2 was abnormally increased in AKI patient renal tubules, correlating with poor prognosis. Similar results appeared in moderate and severe IR mouse models. DcR2-GFP transgenic mice verified that DcR2 was specifically expressed in PTECs and associated with kidney injury. DcR2-CKO improved kidney injury, inhibited cell senescence, promoted cell proliferation and regeneration, and repressed renal fibrosis. Similar results were found in hypoxia/reoxygenation-treated primary PTECs. Four-dimensional proteomics showed that DcR2 modulated tubular senescence by regulating Hmgcs2 (a rate-limiting enzyme of endogenous ketogenesis) expression, thereby affecting renal beta-hydroxybutyrate (β-OHB) levels. Hmgcs2 inhibition or deletion promoted tubular senescence by depleting β-OHB. Nevertheless, β-OHB administration ameliorated these phenomena. Moreover, PTEC-specific DcR2/Hmgcs2 double deletion inhibited Foxo3a by regulating histone acetylation, thereby boosting senescence. We screened out 10 antagonistic peptides of DcR2 (AP-D) using Ph.D.-12 phage display library, and found AP-D8 had the strongest proliferative effect. And AP-D8 effectively inhibited renal interstitial fibrosis and tubular senescence, thereby alleviating AKI.
Conclusion
DcR2 drives AKI progression and tubular senescence by suppressing Hmgcs2-mediated β-OHB production. Targeting DcR2 with AP-D8 effectively mitigates AKI, establishing DcR2 as a promising therapeutic target.