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Life sciences · Journal article
Nutrition and Diabetes · September 16, 2026
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Abstract Aims Obesity is a major risk factor for the development and progression of chronic kidney disease (CKD). Apolipoprotein A4 (Apoa4), a key regulator of lipid and glucose metabolism, also possesses immunomodulatory properties. This study aimed to investigate the role of Apoa4 in renal cellular populations during the early stages of obesity-associated CKD. Methods Wild-type (WT) and Apoa4 knockout (KO) mice were fed a high-fat diet (HFD) to establish an early-stage obesity-associated CKD model. Single-cell RNA sequencing (scRNA-seq) was performed to characterize renal cellular heterogeneity, transcriptional alterations, and intercellular communication. Key findings were further validated using bulk RNA sequencing, histological analyses, and rescue experiments in HFD-fed WT and KO mice. Results Apoa4 deficiency aggravated fibroblast metabolic dysfunction and renal fibrosis, accompanied by reduced fibroblast abundance and impaired extracellular matrix organization, immune regulation, and tissue repair capacity. Cell–cell communication analysis revealed that Apoa4 loss remodeled fibroblast signaling networks. Apoa4-deficient fibroblasts received enhanced pro-growth (ncWNT, EGF), pro-apoptotic (FASLG), and other pathological signaling, while exhibiting diminished responsiveness to immune-activating IFNG signaling from surrounding cells. Conversely, Apoa4 deficiency promoted fibroblast-derived pro-growth IGF and pro-fibrotic THBS signaling toward other renal cell populations, while attenuating anti-fibrotic EDN, immune-regulatory CSF, and immunomodulatory ANGPTL and ANNEXIN signaling. Conclusions Apoa4 deficiency alters renal fibroblast states and fibroblast-mediated intercellular communication during early obesity-associated kidney injury, highlighting a protective role of Apoa4 in maintaining renal microenvironmental homeostasis.