Abstract: FR-PO178
Decoy Receptor 2 Promotes Tubular Maladaptive Repair by Inhibiting Hmgcs2-Induced β-Hydroxybutyrate Production Following AKI
Session Information
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Chen, Jia, Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
- Chen, Kehong, Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
- He, Yani, Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
Background
Tubular maladaptive repair after acute kidney injury (AKI) leads to chronic kidney disease or end-stage renal disease. However, the underlying mechanism remains unclear. The expression of DcR2 was abnormally increased in renal tubules in patients of AKI, and associated with renal prognosis.Similar results were found in moderate and severe ischemia-reperfusion injury and cisplatin-induced AKI mouse models.
Methods
Similar results were found in moderate and severe ischemia-reperfusion injury and cisplatin-induced AKI mouse models. Proteomics analysis and validation study showed that DcR2 mediated maladaptive repair by regulating the expression of Hmgcs2 (a rate-limiting enzyme of endogenous ketogenesis) and the levels of renal beta-hydroxybutyrate (β-OHB). Hmgcs2 inhibition or deletion aggravated kidney damage and repressed renal repair. Nonetheless, β-OHB administration ameliorated these phenomena. Moreover, PTEC-specific DcR2/Hmgcs2 double deletion decreased β-OHB levels, which inhibited FOXO3 by regulating histone acetylation, thereby boosting tubular maladaptive repair.
Results
DcR2-GFP transgenic mice showed that DcR2 was specifically expressed in proximal tubular epithelial cells (PTECs) following AKI, and PTEC-specific deletion of DcR2 improved renal repair and prognosis by alleviating kidney damage, inhibiting cell senescence, promoting cell proliferation and regeneration, and repressing renal fibrosis.
Conclusion
These findings suggest that DcR2/Hmgcs2/β-OHB/FOXO3 signaling mediates tubular maladaptive repair and targeting DcR2 may enhance renal repair and improve AKI prognosis.
Funding
- Private Foundation Support