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Abstract: FR-PO1071

Erythropoietin Prevents TH17 Induction and Sodium Chloride-Driven Kidney Inflammation by Inhibiting SGK1-Dependent IL-17 Production

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Cantarelli, Chiara, University Hospital, Parma, Parma, Italy
  • Angeletti, Andrea, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Donadei, Chiara, Nephrology, Dialysis and Kidney Transplantation, Bologna, Italy
  • Fischman, Clara, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Horwitz, Julian, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • La Manna, Gaetano, Nephrology, Dialysis and Kidney Transplantation, Bologna, Italy
  • Heeger, Peter S., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

High sodium chloride (NaCl) intake worsens kidney pathology by promoting TH17 differentiation. Since erythropoietin (EPO) is predominantly produced in the kidney where NaCl concentrations are high, and because EPO has newly recognized immunoregulatory functions, we tested the hypothesis that kidney-derived EPO prevents TH17 differentiation and thereby modulates TH17-dependent kidney pathology.

Methods

To study the role of endogenous and recombinant EPO on TH17 cells in vivo, we used murine models of kidney disease associated with TH17 induction, including aristolochic acid (ArA) nephropathy (+/- high NaCl diet), MRL-lpr and pristane lupus nephritis models. In vitro studies supplemented by adoptive transfer of naïve or TH17 cells into rag1-/- mice were used to determine the direct role of EPO on TH17 induction (Figure 1A).

Results

Recombinant EPO and transgenic EPO overexpression limited pathology, while in vivo shRNA-induced EPO downregulation augmented ArA-induced TH17 formation and the clinical expression of disease. Recombinant EPO administration also prevented development of glomerular disease in lupus models, clinical results that were associated with reduced frequencies of TH17 cells. In rag1-/- adoptive transfer experiments, EPO directly inhibited in vivo TH17 development (Figure 1B-C) and promoted trans-differentiation of TH17 into regulatory T cells. Using murine and human T cells, we then showed that EPO ligation of its T cell-expressed receptor abrogated NaCl-induced upregulation of Sgk1 gene expression and blocked p38 activity to prevent SGK1 phosphorylation, thereby limiting RORC induction and TH17 differentiation.

Conclusion

EPO physiologically and therapeutically inhibits TH17 cell differentiation and TH17-associated autoimmune kidney pathology by antagonizing intracellular signaling pathways required for NaCl-driven TH17 differentiation.

Funding

  • NIDDK Support