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Kidney Week

Abstract: PO0412

The Role and Mechanism of DcR2-Positive Failed Repair Cells in AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Chen, Jia, Daping Hospital, Army Medical University, Chongqing, China
  • He, Yani, Daping Hospital, Army Medical University, Chongqing, China
Background

Acute kidney injury (AKI) is a common clinical emergency and critical illness. The regeneration and repair of renal tubular cells determine the prognosis of AKI. Our previous study found that decoy receptor 2 DcR2, a senescent marker, was specifically expressed renal tubules and did not have the ability to proliferate in AKI, suggesting DcR2 may be associated with repair of tubular cells. This study aims to investigate the role and mechanism of DcR2-positive tubular cells in AKI.

Methods

The DcR2-GFP lineage trace mice, KSP-creDcR2f/f and GGT1-creDcR2f/f mice and Ischemia-Reperfusion (I/R) Injury models were constructed. Confocal analysis the co-expression of DcR-GFP and proximal tubular markers(AQP1, Villin), distal markers (AQP2), failed repair markers (Vcam1, Dcdc2), proliferative markers (Ki-67, Edu, PCNA), Kim1, differentiated markers (pax2, sox9,six2), senescent markers (P16, P21, SA-β-gal) and fibrotic markers (a-SMA,collagen I, Fibronectin). And wild type (WT) mice and DcR2 CKO mice were used to compar the degree of renal tissue, functional damage and tubular repair after I/R injury. Furthermore, quantitative proteomics analyzed the downstream molecules of DcR2 in renal tissues from WT-AKI and CKO-AKI, and validated studied were done.

Results

The DcR2-GFP were mainly expressed proximal tubular cells in AKI. DcR2-GFP positive cells were co-expressed failed repair markers, senescent markers and co-localization with fibrotic markers. And DcR2-GFP positive cells were not expressed Kim1, proliferative and differentiated markers. The levels of Scr, BUN and renal injury scores were significantly lower in GGT1-creDcR2f/f -AKI than that of WT-AKI. Meanwhile, the area of renal fibrosis and fibrotic markers expression was decreased. However, the above phenomenon of KSP-creDcR2f/f–AKI were not obviously improved. Additionally, quantitative proteomics and validated studies showed HMGCS2, a key enzyme for Ketone Synthesis, was increased in GGT1-creDcR2f/f mice compared with WT. And the levels of urinary and serum β-hydroxybutyrate were higher in GGT1-creDcR2f/f mice.

Conclusion

DcR2-positive tubules were failed-repair cells in AKI. And DcR2 promotes failed repair of tubular cells through regulating the expression of HMGCS2 then affects the metabolism of β-hydroxybutyrate, suggesting that DcR2 may be a potential intervention target during the progression of AKI.

Funding

  • Government Support – Non-U.S.