The P2X7 purinergic receptor is emerging as a key regulator of inflammation. Genetic and pharmacological blockade of this ATP-gated ion channel have shown clinical benefit in rodent models of nephrotoxic nephritis. However, the precise role of P2X7 on inflammatory cells and on resident kidney cells during glomerulonephritis remain largely unknown. Our group has generated functional nanobodies (single domain antibodies) against P2X7. In the mouse model of anti-podocyte nephritis, we found that P2X7-blocking nanobodies ameliorate disease whereas P2X7-agonistic nanobodies potentiate disease. A central goal of the proposed project is to elucidate the role of P2X7 on infiltrating inflammatory cells and on resident kidney cells in nephrotoxic and anti-podocyte nephritis and to evaluate the therapeutic potential of P2X7-antagonizing nanobodies in these diseases. Antibodies directed against the podocyte membrane protein THSD7A have recently been shown to play a pathogenic role in membranous nephropathy in humans and mice. A further goal of the project is to develop therapeutic nanobodies that block the binding of pathogenic autoantibodies to THSD7A.

We expect that the results of our project will shed new light on the role of P2X7 on infiltrating inflammatory and on resident kidney cells. Moreover, the results will help pave the way for new, nanobody-based therapeutics of glomerulonephritis.

Linden, Koch-Nolte, Dahl. 2019. Purine Release, Metabolism and Signaling in the Inflammatory Response. Ann. Rev. Immunol. 13:17.