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Abstract: SA-PO101

Mechanism of Immunogenicity Change of Renal Tubular Epithelial Cells Induced by MDM2 Membrane Translocation in Ischemic AKI

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Zeng, Jieyu, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Su, Hua, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Zhang, Chun, Huazhong University of Science and Technology, Wuhan, Hubei, China
Background

Increased immunogenicity of proximal tubular epithelium (PTE) contributes to donor acute kidney injury (AKI) associated TCMR. Formerly, we found MDM2, an E3 ubiquitin ligase, translocated from cytosol to basolateral membrane of tubules during AKI. To explore the underlying relationship between MDM2’s translocation and tubular immunogenicity will provide reliable clues to alleviating the shortage of donor as well as preventing the loss of graft.

Methods

AKI was induced by ischemia/reperfusion treatment in 8-week C57BL/6 mice. After 45 minutes of bilateral renal pedicle clamping, they were divided into sham, 2 days and 4 days groups according to the time of reperfusion. The expression and distribution of MDM2 and PD-L1 were analyzed by immunostaining and Western blot. In vitro, NRK-52E cells were cultured in a hypoxic environment for different time points (1% O2) followed by reoxygenation, and mutated MDM2 plasmid were utilized to interfere the subcellular transportation of MDM2.

Results

The distribution of MDM2 gradually shifts to basolateral membrane after renal IRI. Moreover, in IRI groups the abundance of PD-L1, known as a T cell inhibitory co-stimulatory molecule, is weaken significantly. In vitro, by oxygen-glucose deprivation or genetic interfering techniques we demonstrated that MDM2’s trafficking attributes to PD-L1 degradation during hypoxia.

Conclusion

During ischemic AKI or hypoxia, the translocation of tubular MDM2 leads to basolateral PD-L1 degradation which consequently results in the downregulated inhibitory co-stimulatory signaling with T cell activation.

Funding

  • Government Support – Non-U.S.