Kidney Week

Abstract: FR-PO1071

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

Session Information

• Glomerular Diseases: Immunology and Inflammation - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Cantarelli, Chiara, University Hospital, Parma, Parma, Italy

Chiara Cantarelli,

• Angeletti, Andrea, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Andrea Angeletti,

• Donadei, Chiara, Nephrology, Dialysis and Kidney Transplantation, Bologna, Italy

Chiara Donadei,

• Fischman, Clara, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Clara Fischman,

• Horwitz, Julian, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Julian Horwitz,

• La Manna, Gaetano, Nephrology, Dialysis and Kidney Transplantation, Bologna, Italy

Gaetano La Manna,

• Heeger, Peter S., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Peter S. Heeger,

• Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Paolo Cravedi,

Background

High sodium chloride (NaCl) intake worsens kidney pathology by promoting T_H17 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 T_H17 differentiation and thereby modulates T_H17-dependent kidney pathology.

Methods

To study the role of endogenous and recombinant EPO on T_H17 cells in vivo, we used murine models of kidney disease associated with T_H17 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 T_H17 cells into rag1^-/- mice were used to determine the direct role of EPO on T_H17 induction (Figure 1A).

Results

Recombinant EPO and transgenic EPO overexpression limited pathology, while in vivo shRNA-induced EPO downregulation augmented ArA-induced T_H17 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 T_H17 cells. In rag1^-/- adoptive transfer experiments, EPO directly inhibited in vivo T_H17 development (Figure 1B-C) and promoted trans-differentiation of T_H17 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 T_H17 differentiation.

Conclusion

EPO physiologically and therapeutically inhibits T_H17 cell differentiation and T_H17-associated autoimmune kidney pathology by antagonizing intracellular signaling pathways required for NaCl-driven T_H17 differentiation.

Funding

• NIDDK Support