Dapagliflozin Reduces Kidney Inflammation in Alport Syndrome by Inhibiting the Stimulator of IFN Genes Pathway in Renal Tubular Epithelial Cells

KEY POINTS: Dapagliflozin reduces proteinuria in patients with Alport syndrome. Dapagliflozin plays an anti-inflammatory role by inhibiting the stimulator of IFN genes pathway in tubular epithelial cells of Alport syndrome mice. BACKGROUND: Alport syndrome (AS) is a hereditary kidney disease caused by COL4A3/4/5 mutations that lack of effective treatments. Sodium-glucose cotransporter 2 inhibitors have demonstrated renal and cardiovascular protective effects in patients with CKD; however, their long-term effects in patients with AS and the underlying mechanisms remain to be clarified. METHODS: We conducted a single-arm, prospective study to examine the effect of dapagliflozin in patients with AS. In parallel, Col4a3 p.C1615Y-mutant mice (129S2/Sv background) were used as an AS model to investigate the renoprotective mechanisms of dapagliflozin. RESULTS: A total of twenty-one patients with AS were enrolled. After approximately 12 months of follow-up (12.6±1.2 months), the mean 24-hour urinary protein decreased by 29% to 1.25±0.73 g from baseline (1.75±0.90; P < 0.001). The eGFR showed no significant difference compared with baseline (76±28 versus 77±29 ml/min per 1.73 m 2 , P = 0.57). In the animal studies, dapagliflozin significantly reduced macrophage infiltration and the expression of inflammatory cytokines levels in the renal cortex of Col4a3 -mutant mice. Mechanistic studies showed that stimulator of IFN genes (STING) pathway was activated in the renal cortex and tubular epithelial cells (TECs) from Col4a3 mice, contributing to a proinflammatory phenotype. Dapagliflozin effectively inhibited STING activation and suppressed inflammatory cytokines production in mutant TECs. CONCLUSIONS: Dapagliflozin can reduce proteinuria in patients with AS and plays an anti-inflammatory role by inhibiting the STING pathway in TECs of AS mice.