Canagliflozin Alleviates Experimental Antineutrophil Cytoplasmic Antibody-Associated Vasculitis through Suppression of Pathogenic T-Cell Responses.

Abstract

The nephroprotective role of sodium-glucose cotransporter 2 (SGLT2) inhibitors has been well-established by several randomized controlled trials (RCTs) involving patients with diabetic and non-diabetic chronic kidney disease. However, the impact of SGLT2 inhibitors on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the underlying mechanisms remain unclear. The therapeutic effects of canagliflozin were evaluated in a rat model of experimental AAV. RNA sequencing was performed on the kidney and lymph nodes. In parallel, mechanistic studies were conducted in mouse models. Myeloperoxidase (MPO) deficient (Mpo-/-) mice were immunized with mouse MPO and treated with canagliflozin. Splenocytes from these donors were then adoptively transferred into recombinase-activating gene-1 deficient (Rag1-/-) mice. Comprehensive immune phenotyping by flow cytometry, enzyme-linked immunospot (ELISpot) assays, and in vitro differentiation of human T cells were employed to dissect the immunomodulatory effects and underlying mechanisms. Canagliflozin alleviated kidney injury, pulmonary hemorrhage and T lymphocyte infiltration in AAV rats. Renal transcriptomic analysis showed a suppression of adaptive immunity pathways. In the adoptive transfer model, canagliflozin treatment of donor mice led to a significant reduction in splenic Th1, Th17, and CD8+ T cells, accompanied by a markedly diminished capacity of splenocytes to secrete IFN-γ and IL-17A upon restimulation. Transfer of these modulated splenocytes conferred significant nephroprotection to recipient mice. In vitro, canagliflozin suppressed the differentiation of primary CD4+ T cells from patients with AAV into both Th1 and Th17 lineages, but did not directly affect B cell activation or antibody production. Mechanistically, canagliflozin inhibited the phosphorylation of both p38 and ERK MAPKs in activated T cells, and the suppressive effect on cytokine production was partially reversed by activation of the p38 MAPK pathway. Canagliflozin alleviated experimental AAV by suppressing pathogenic T cell effector responses-an effect mechanistically linked to inhibition of the p38 signaling pathway.