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Kidney Week

Abstract: PO0153

ST2/IL33 Signaling Axis in Tregs Critical for Restoring Kidney Tissues Homeostasis on Injury

Session Information

  • AKI Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sabapathy, Vikram, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Cheru, Nardos Tesfaye, National Institutes of Health, Bethesda, Maryland, United States
  • Price, Airi, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Venkatadri, Rajkumar, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Dogan, Murat, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Mohammad, Saleh, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Stevens, Brian K., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background

Renal diseases are a major cause of morbidity and mortality worldwide. Thus, leading to a great financial burden on health care systems. Inflammation elicited by a variety of cytokines and chemokines is a major player in the initiation and progression of the disease. Interleukin 33 (IL-33) acts as an ‘alarmin’ that regulates the immune response during injury. IL-33 acts in an autocrine/paracrine manner through membrane receptor (ST2) aka IL33R or IL-1 receptor-like 1 (IL1RL1), triggering an innate and adaptive immune response. There is no evidence determining the importance of the ST2/IL33 axis in Tregs during kidney injury. In this study, we attempt to delineate the role of the ST2/IL33 pathway in Tregs cells using murine renal injury models and kidney organoids.

Methods

Murine ischemia-reperfusion injury (IRI) model was used to investigate the importance of cell-specific ST2/IL-33 signaling using IL1RL1tm1a and Foxp3 cre mice to delete ST2 expression in Tregs. RNA sequencing analysis, flow cytometry, histology, immunohistochemistry, quantitative gene expression, and biochemical analysis were applied to dissect the role of ST2/IL33 signaling. Kidney organoid based 3D cell culture platform was used to setup co-culture experiments with ST2-/- and ST2+/+ Tregs for invitro evaluation.

Results

The RNA sequencing analysis of ST2-High Tregs indicated higher expression of regenerative factors such as amphiregulin (AREG) and Growth/differentiation factor (GDF15). The in vivo renal injury experimental data indicated that elimination of ST2/IL33 signaling from Tregs resulted in exacerbation of renal injury leading to worsening of renal function as determined by plasma creatinine, blood urea nitrogen, kidney injury markers (kim1 and Ngal) and fibrosis markers (Col1a1, Col3a1, SMA, and vimentin). Co-culture of kidney organoids with ST2+/+ expressing Tregs protected organoids from cellular apoptosis under invitro ischemia-reoxygenation conditions compared to ST2-/- Tregs.

Conclusion

Impairment of ST2/IL33 signaling in Tregs leads to worsening of renal function following ischemic injury. This indicating that activation of ST2/IL33 signaling in Tregs mediate in the regulation of inflammation, apoptosis, and repair in renal tissue during inflammation and injury.

Funding

  • NIDDK Support