Macrophage IgG Recycling Couples Glomerular IgG Accumulation to Podocyte Senescence in Obesity-Related Glomerulopathy

BACKGROUND: Obesity-related glomerulopathy is increasingly common, yet its pathogenesis remains poorly understood. This study aimed to elucidate the mechanisms by which nonspecific glomerular IgG deposition promotes podocyte senescence in obesity-related glomerulopathy, thereby expanding potential therapeutic options. METHODS: Kidney samples from patients with obesity-related glomerulopathy and diet-induced obese mice were used to compare glomerular IgG localization and abundance in obese versus control states. Causality between glomerular IgG accumulation and podocyte senescence was assessed by exogenous IgG supplementation and B cell deficiency mice. Primary podocytes were IgG-stimulated for transcriptomic and lipidomic profiling, and sphingomyelin phosphodiesterase 3 (Smpd3) was validated by in vitro and in vivo loss-of-function studies. Macrophage-specific FcRn deletion and anti-CD20 therapy were further used to evaluate IgG-targeted strategies for mitigating podocyte senescence and injury in ORG. RESULTS: Glomerular IgG deposition was markedly increased in both patients with obesity-related glomerulopathy and mice with diet-induced obesity. Exogenous IgG supplementation in non-obese mice reproduced the glomerular IgG accumulation and podocyte senescence observed in HFD fed mice. Conversely, B-cell null diet-induced obese mice and anti-CD20 treated diet-induced obese mice showed greatly reduced glomerular IgG levels and attenuated podocyte injury. Mechanistically, IgG exposure activated podocyte sphingolipid metabolism, notably upregulating Smpd3 and increasing intra-podocyte ceramide. In vitro and in vivo Smpd3 knockdown prevented IgG induced ceramide accumulation and podocyte senescence. Obesity also heightened glomerular macrophage infiltration, and macrophage depletion or macrophage-specific FcRn knockout significantly reduced glomerular IgG deposition and protected against podocyte injury and senescence. CONCLUSIONS: FcRn-expressing macrophages increased obesity-induced IgG retention in glomeruli, which led to podocyte ceramide overload and senescence.