Abstract

Hypobaric hypoxia, a unique environmental feature of high-altitude areas, is associated with kidney disease, but the mechanism remains unclear. In this study, blood and urine samples from high-altitude volunteers are examined, revealing that high-altitude hypoxia causes kidney injury. Renal fibrosis developed in C57BL/6 mice following 28 days of hypobaric hypoxia, suggesting Wnt5b involvement in fibrogenesis under hypoxic conditions. Wnt5b knockdown ameliorates hypoxia-induced renal fibrosis in vivo . NRK-52E cells undergo partial epithelial-mesenchymal transition and produce more Wnt5b under hypoxic conditions. Wnt5b secreted by NRK-52E cells via exosomes activates canonical Wnt signaling in NRK-49F cells. This activation requires cooperation between FZD1 and LRP6 receptors, which trigger β-catenin cytoplasmic stabilization and nuclear translocation, driving fibroblast activation. These findings suggest that intercellular communication between renal epithelial and mesenchymal cells via the Wnt5b/β-catenin pathway promotes renal fibrosis development under high-altitude hypoxia. This study uncovers the mechanisms underlying renal fibrosis and proposes promising therapeutic targets for altitude-induced kidney disease.