Canagliflozin Alleviates Experimental ANCA-Associated Vasculitis through Suppression of Pathogenic T-Cell Responses

KEY POINTS: Canagliflozin ameliorated experimental ANCA-associated vasculitis through broad suppression of pathogenic T-cell subsets. The immunomodulatory effect of canagliflozin was mediated in part by inhibition of p38 mitogen-activated protein kinase signaling in T cells. BACKGROUND: The nephroprotective role of sodium-glucose cotransporter 2 (SGLT2) inhibitors has been well established by several randomized controlled trials involving patients with diabetic and nondiabetic CKD. However, the impact of SGLT2 inhibitors on ANCA-associated vasculitis (AAV) and the underlying mechanisms remain unclear. METHODS: 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-deficient ( Mpo-/- ) mice were immunized with mouse myeloperoxidase 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 assays, and in vitro differentiation of human T cells were employed to dissect the immunomodulatory effects and underlying mechanisms. RESULTS: 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 extracellular signal-regulated kinase mitogen-activated protein kinases in activated T cells, and the suppressive effect on cytokine production was partially reversed by activation of the p38 mitogen-activated protein kinase pathway. CONCLUSIONS: Canagliflozin alleviated experimental AAV by suppressing pathogenic T cell effector responses-an effect mechanistically linked to inhibition of the p38 signaling pathway.