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Kidney Week

Abstract: FR-PO102

Enhancement of Tregs with IL233 Hybrid Cytokine Rescues Kidney Function in Aristolochic Acid-Induced Nephropathy

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Dogan, Murat, Division of Nephrology and CIIR, Charlottesville, Virginia, United States
  • Venkatadri, Rajkumar, University of Virginia, Charlottesville, Virginia, United States
  • Sabapathy, Vikram, The Rector and Visitors of the University of Virginia, Charlottesville, Virginia, United States
  • Stevens, Brian K., University of Virginia, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States

Group or Team Name

  • Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia
Background

Aristolochic acid (AA) is used as a “traditional medicine” to induce labor and for treatment of arthritis and inflammation. The Balkan nephropathy is supposedly caused by chronic dietary consumption of AA and genetic predisposition. However, recent studies showed that consumption of AAleads to tubular epithelial cell (TEC) injury and inflammation, which triggers acute and chronic renal dysfunction. Our goal in this study was to investigate the role of T-regulatory cells (Tregs) and susceptibility of TEC in experimental AA nephropathy.

Methods

We induced renal injury in male C57Bl/6 mice with AA injection (i.p.) and evaluated the progression of acute nephropathy for 4 weeks. Additionally, PC61 (anti-CD25 Ab to deplete Tregs) and IL233 (a novel Treg-enhancing hybrid cytokine bearing the activities of IL-2 and IL-33) were appliedto evaluate the progression of nephropathy.Sera samples were collected and used for plasma creatinine (PCr) and blood urea nitrogen (BUN) assessment with the commercially available kits. Tubular necrosis in the kidneys was assessed on H&E sections. KIM-1 and NGAL were used for kidney injury markers. Flow cytometry was used to evaluate inflammatory cells and cytokine profile in kidneys, spleen and blood. The effect of IL233 in PD1 and IL-33R (ST2) KO mice in AA nephropathy was also studied to understand the underlying mechanisms. All animal procedures and personnel were approved by institutional animal care and care committee.

Results

Mice treated with AA developed severe renal dysfunction, inflammation and tubular necrosis. Immune cells were elevated alongside renal inflammation. Administration of anti-CD25 mAb PC61 worsened renal dysfunction in AA-treated mice, increased the susceptibility of mice to AA-induced nephrotoxicity, suggesting a role of Tregs. Treatment of mice withIL233 (a Treg-enhancing hybrid cytokine containing IL-2 and IL-33), after the onset of injury suppressed inflammation, renal dysfunction and injury, evident by the reduced levels of plasma creatinine, BUN and in these animals, whereas PC61 mAb ameliorated the IL233-mediated protection indicating Tregs as primary immune cells rendering protection.

Conclusion

IL233 protects from AA induced nephrotoxicity in a Treg-dependent manner with a role for ST2 and PD-1, and bears therapeutic potential.

Funding

  • Other NIH Support