Single-cell transcriptomics reveals apolipoprotein A4-mediated metabolic-immune reprogramming in lymphocytes during early obesity-related chronic kidney disease

Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and <i>Apoa4</i>-knockout (KO) mice. KO mice exhibit exacerbated insulin resistance and renal lipid accumulation. Single-cell RNA sequencing reveals that <i>Apoa4</i> deletion remodeled the renal immune-metabolic landscape. This remodeling broadly compromises the immune functions of T, NK, and B cells, even as it expands the proportions of cytotoxic Gzma ⁺ NK cells and Derl3 ⁺ plasma cells. Mechanistically, <i>Apoa4</i> deletion aggravates metabolic dysregulation and oxidative stress and downregulates the expression levels of key effector genes, including <i>Ifng</i> and <i>Il1b</i>. Furthermore, the regulatory network activities of key transcription factors, such as <i>Lef1</i> and <i>Runx3</i> in Cd8 ⁺ T cells; <i>Irf8</i>, <i>T-bet</i>, and <i>Eomes</i> in NK cells; and <i>Tcf4</i>, <i>Lmo2</i>, and <i>Xbp1</i> in B cells, are perturbed. CellChat analysis predicts disruptions in pro-inflammatory (IFN-II and IL-1), immunoregulatory (FASLG), and metabolic regulatory (ENHO and ANGPTL) signaling, alongside enhanced IL-2-mediated suppression. These findings are corroborated by flow cytometry, immunofluorescence staining, and qPCR. Our results establish Apoa4 as a crucial regulator of lymphocyte metabolic and immune homeostasis in the early stages of obesity-associated CKD.