Macrophage IgG recycling couples glomerular IgG accumulation to podocyte senescence in obesity-related glomerulopathy

ABSTRACT: Background: Obesity-related glomerulopathy (ORG) 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 ORG, thereby expanding potential therapeutic options. Methods: ORG patient samples and diet-induced obese (DIO) 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. Primary podocytes were IgG-stimulated for transcriptomic and lipidomic profiling, and 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: In ORG patient kidneys and DIO mice, glomerular IgG deposition was markedly increased. Exogenous IgG supplementation in non-obese mice reproduced the glomerular IgG accumulation and podocyte senescence observed in HFD fed mice. Conversely, B null DIO mice and anti-CD20 treated DIO 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 mediate obesity-induced IgG retention in glomeruli, which drives podocyte ceramide overload and senescence.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS14881 | MetaboLights | 2026-06-28

REPOSITORIES: MetaboLights