Acetate ameliorates membranous nephropathy by modulating the immune response and podocyte function

Membranous nephropathy (MN) is an antibody-mediated podocytopathy in which subepithelial immune deposits and complement activation lead to podocyte injury and proteinuria. Short-chain fatty acids (SCFAs) are microbiota-derived metabolites with immunomodulatory properties, but their therapeutic potential and mechanisms in MN remain incompletely defined. We evaluated acetate, propionate, and butyrate in a passive Heymann nephritis (PHN) rat model ( n = 6/group). Rats received 150 mM sodium acetate, propionate, or butyrate in drinking water from day 0 to day 42. Proteinuria and biochemical indices were monitored; glomerular immune deposition and ultrastructure were assessed by immunofluorescence and transmission electron microscopy. Antigen-specific antibodies were quantified by ELISA. Glomerular expression of synaptopodin and WT1 was detected by immunohistochemistry. Splenic CD4 + T-cell subsets were analyzed by flow cytometry. In vitro, conditionally immortalized human podocytes were exposed to plasma from patients with primary MN, with or without acetate and the GPR43 antagonist GLPG0974, migration, synaptopodin expression, reactive oxygen species (ROS), apoptosis, and viability were assessed, and SCFA receptor expression was examined. All three SCFAs significantly reduced proteinuria in PHN rats compared with disease controls and ameliorated ultrastructural injury, including GBM thickening and podocyte foot-process effacement. Acetate and propionate reduced subepithelial immune-complex deposits. Acetate selectively decreased antigen-specific anti-sheep IgG responses without altering total IgG. PHN was associated with decreased Tregs and increased Th1/Th17 polarization; acetate increased the Treg proportion in splenocytes. Acetate protected podocyte cytoskeletal integrity and viability in vivo. Acetate acted through GPR43, as the GPR43 antagonist GLPG0974 partially or completely blocked acetate’s effects on ROS reduction, migration improvement, and synaptopodin mRNA upregulation. Acetate treatment reduced HDAC activity in both renal cortex and podocytes while increasing HAT activity. Acetate mitigated primary MN plasma–induced dysfunction by improving migration and synaptopodin signal, reducing ROS, limiting apoptosis, and restoring cell viability. Acetate ameliorates experimental MN through coordinated immunomodulatory effects and amelioration of podocyte foot process effacement. These findings support targeting acetate pathways as a mechanistically plausible adjunct strategy with low potential toxicity for MN.