Abstract: TH-PO317

Role of MIF2 in Proximal Tubular Cell Proliferation and Survival after Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Ochi, Akinobu, Yale University School of Medicine, New Haven, Connecticut, United States
  • Chen, Dong, Yale University School of Medicine, New Haven, Connecticut, United States
  • Averdunk, Luisa, RWTH Aachen University, Aachen, Germany
  • Piecychna, Marta, Yale University School of Medicine, New Haven, Connecticut, United States
  • Du, Xin, Yale University School of Medicine, New Haven, Connecticut, United States
  • Leng, Lin, Yale University School of Medicine, New Haven, Connecticut, United States
  • Bucala, Richard, Yale University School of Medicine, New Haven, Connecticut, United States
  • Moeckel, Gilbert W., Yale University School of Medicine, New Haven, Connecticut, United States
Background

Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions including cell proliferation and survival. MIF is expressed in kidney tubular cells and released by various stimuli such as hypoxia. Renal tubular cells express MIF receptors: CD74/44, CXCR2/4. Recently D-dopachrome tautomerase, also known as MIF2 was characterized as a homologue of MIF. MIF2 is thought to exert more selective tissue protective action via CD74 activation than MIF. We examined the role of MIF2 in renal tubular cell proliferation and survival after ischemia-reperfusion (I/R) injury.

Methods

Mif-/-, Mif2-/-, Cd74-/- and wild type (WT) mice were subjected to 30 minutes bilateral I/R surgery. We then injected MIF2 intraperitoneally every 12 hours. We collected kidney and blood samples 48 hours after I/R surgery, and evaluated tubular damage and performed comprehensive RNAseq analysis. For in vitro modeling of I/R injury, we used mouse MPT proximal tubular cells incubated in a hypoxic chamber (0.1% O2, 6 hrs, low nutrient medium). The cells then were cultured in normal condition with/without 100 ng/ml of MIF2 for different time points.

Results

Mif-/-, Mif2-/- and CD74-/- mice had more severe tubular injury compared to WT mice. MIF2 injection promoted proximal tubular cell proliferation and improved renal function. RNAseq analysis showed that MIF2 injection increased cell cycle associated genes (cyclinD1, D2, E1, E2), secretory leukocyte proteinase inhibitor (SLPI) and survivin expression. In MPT cells, MIF2 promoted cell proliferation via cyclin D1 upregulation following SLPI upregulation in 36 hours. The short time (30-120 min) impact of MIF2 on hypoxic MPT cells included activation of eIF2α and ATF4, which are involved in the integrated stress response. MIF2 also induced autophagy and inhibited apoptosis.

Conclusion

MIF2 promoted renal tubular cell proliferation and survival after I/R injury. MIF2 may be of therapeutic utility as a regenerative agent in the clinical setting of ischemic acute kidney injury.

Funding

  • Other NIH Support