Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, being driven by incompletely understood autoimmune mechanisms. Emerging evidence suggests that γ-aminobutyric acid (GABA), traditionally considered a neurotransmitter, also functions as a critical immunomodulator in peripheral tissues. Dysregulation of GABAergic signaling has been linked to altered immune cell trafficking and metabolic stress in renal pathologies. However, its specific role and signature genes in MN pathogenesis have not been systematically characterized. This study aimed to identify novel GABA-associated biomarkers for MN and elucidate their potential mechanistic roles. By integrating differential expression analysis, weighted gene coexpression network analysis, and machine learning algorithms on public transcriptomic datasets, we identified three robust GABA-associated candidate biomarkers: AP2S1, STXBP1, and GNGT2. These genes were consistently upregulated in patients with MN across both the training and validation cohorts. Functional enrichment analysis revealed their significant involvement in vesicle trafficking, cytochrome P450 metabolism, and cell adhesion pathways. Immune infiltration analysis demonstrated that these biomarkers had strong positive correlations with central memory CD4 + T cells and myeloid-derived suppressor cells. Furthermore, molecular docking simulations indicated high binding affinities between these targets and potential therapeutic compounds, including valproic acid and genistein. Crucially, reverse transcription quantitative polymerase chain reaction validation in an independent clinical cohort (n = 10) confirmed significantly elevated expression of AP2S1, STXBP1, and GNGT2 in the peripheral blood of patients with MN versus healthy controls (P < 0.05). This study established a distinct GABAergic signature in MN, highlighting AP2S1, STXBP1, and GNGT2 as promising noninvasive diagnostic biomarkers. Our findings suggested that GABA-related vesicle trafficking and metabolic pathways contribute to the autoimmune microenvironment in MN. These genes offer new avenues for early diagnosis and represent potential therapeutic targets for precision medicine strategies in managing MN.
Luo et al. (Wed,) studied this question.