YS-1301 ameliorates crescentic glomerulonephritis by promoting immunoregulatory macrophages

BACKGROUND: Anti-glomerular basement membrane (GBM) glomerulonephritis (GN) is a severe crescentic GN causing rapid renal failure. Despite extensive study of leukocyte-mediated injury, effective therapies that suppress inflammation and promote immunoregulation remain limited. YS-1301, a non-prostanoid prostacyclin receptor agonist and thromboxane synthase inhibitor, enhances tissue-protective factor release and modulates immune responses in other disease models. This study investigated whether YS-1301 ameliorates anti-GBM GN via immunomodulatory mechanisms. METHODS: Crescentic GN was induced in WKY rats by intravenous injection of anti-GBM antibody clone TF78. YS-1301 (10 mg/kg/day) was administered intravenously after disease induction on days 0-2. Renal function and histologic injury were assessed on day 3, and additional cohorts were evaluated on day 7, the latest time point within the rapidly progressive GN phase of this model. Leukocyte infiltration and monocyte/macrophage phenotypes were evaluated by immunohistochemistry and flow cytometry. RESULTS: cell numbers increased. Flow cytometry confirmed that YS-1301 promoted enrichment of immunoregulatory/pro-resolving monocyte/macrophage populations, thereby shifting leukocytes toward an immunoregulatory state. CONCLUSIONS: When administered as an early post-induction intervention, YS-1301 ameliorated anti-GBM GN and was associated with localized accumulation of glomerular immunoregulatory macrophages rather than reduced total macrophage infiltration. These data support further evaluation of YS-1301 as an early immunomodulatory strategy for rapidly progressive GN.