Circulating ANGPTL4 predicts CKD and ESKD risk: insights from large-scale proteomics and senescence mechanisms

Abstract Background The global burden of chronic kidney disease (CKD) is increasing significantly, with aging recognized as a major risk factor associated with accelerated biological aging and poor renal outcomes. Growing evidence links angiopoietin-like protein 4 (ANGPTL4) to both aging and CKD pathogenesis, suggesting its potential as a therapeutic target and warranting further exploration. Methods We analyzed 53,014 UK Biobank participants with complete data in a human cohort study, employing multivariate Cox regression, Pearson correlation, and mediation analysis, and validated the findings in an external cohort. To investigate the role of ANGPTL4 in CKD, we established two mouse models: 5/6 nephrectomy-induced CKD and unilateral ureteral obstruction (UUO). We injected AAV9-carrying ANGPTL4 via the tail vein to overexpress it in UUO mice and utilized ANGPTL4 −/− mice for loss-of-function studies. In vitro senescence models in HK-2 cells, combined with single-cell RNA sequencing of kidney tissues, were used to pinpoint the cellular source and downstream pathway. Results Our study delineates the multifaceted roles of ANGPTL4 in CKD. Analysis of the UK Biobank database revealed a negative correlation between serum ANGPTL4 levels and estimated glomerular filtration rate (eGFR). Elevated ANGPTL4 levels were observed in CKD patients, as well as in age-related CKD subgroups including hypertensive nephropathy, diabetic nephropathy, and membranous nephropathy. For each standard deviation (SD) increase in ANGPTL4 levels, the risk of developing CKD increased by 22.7%. Higher ANGPTL4 levels were also associated with CKD-related frailty, mortality, heart failure, and atherosclerotic diseases, and showed positive correlations with aging and pro-inflammatory/fibrotic factors. In vivo, ANGPTL4 expression was upregulated in both 5/6 nephrectomy (Nx) and UUO mouse models. Genetic knockout of ANGPTL4 alleviated renal injury, whereas its overexpression exacerbated renal fibrosis. Functionally, ANGPTL4 synergized with D-galactose to induce tubular cell senescence in vitro, a process mediated through activation of the PI3K/AKT/mTOR pathway. Conclusion ANGPTL4 is a pivotal driver of CKD progression, primarily by promoting senescence in renal tubular epithelial cells, underscoring its potential as a therapeutic target for CKD.