Lead acetate exposure alters renal water reabsorption and gut microbiota in mice: Potential involvement of cerebral cavernous malformations 3 and the gut–kidney axis

Lead is a widespread, cumulative environmental pollutant with confirmed renal and gastrointestinal toxicity, but the mechanism underlying lead-induced alterations in renal water reabsorption and the potential role of the gut–kidney axis remain unclear. This study aims to explore the potential role of cerebral cavernous malformations 3 (CCM3) in lead-induced alteration of renal tubular water reabsorption and its potential association with the gut–kidney axis. C57BL/6J mice were administered drinking water containing 0.05%, 0.25%, and 0.5% lead acetate for 30 days. Urine was collected weekly for quantitative analysis. After exposure, a desmopressin (dAVP) challenge test was performed. Blood lead concentration was detected by inductively coupled plasma mass spectrometry. Kidney tissues were evaluated by hematoxylin and eosin (H&E) staining and Western blot. Fecal samples were collected before and after exposure for 16S rRNA gut microbiota sequencing. Data were analyzed by repeated-measures analysis of variance (ANOVA) and one-way ANOVA using GraphPad Prism 8.0. As exposure dose increased, blood lead concentration increased dose-dependently in all exposure groups. Urine output decreased significantly in medium- and high-dose groups after 24-hour water deprivation and dAVP challenge. H&E staining showed dose-dependent renal tubular necrosis. The composition and diversity of gut microbiota were significantly altered. Renal CCM3 protein expression was significantly increased (most prominent in the medium-dose group), glutathione peroxidase 4 (GPX4) protein was significantly decreased in the high-dose group, and aquaporin (AQP) 2 and AQP4 proteins showed an upward trend without statistical significance. Lead exposure induces renal tubular structural injury and alters renal water reabsorption function. This process may be associated with gut microbiota dysbiosis, which affects renal CCM3 expression via the gut–kidney axis and further regulates AQP2/4 levels through GPX4-related pathways. This study provides preliminary correlational evidence and proposes a testable hypothesis for future mechanistic research.