Preliminary evidence for the association of elevated indole-3-acetic acid with high-altitude kidney injury: An exploratory study of AhR activation and synergistic effects with hypoxia

High-altitude hypoxia induces multisystem adaptive changes, yet its impact on the gut-kidney axis remains poorly understood. In this exploratory pilot study, we investigated the potential role of indole-3-acetic acid (IAA), a uremic toxin derived from tryptophan metabolism, in high-altitude-associated kidney injury. Untargeted metabolomics revealed an association between elevated IAA levels and renal function parameters: serum, urinary, and fecal IAA levels were significantly higher in high-altitude residents (> 4000 m) compared with lowland controls (< 500 m). In the pooled analysis, serum IAA was inversely correlated with eGFR ( r = -0.687, P < 0.001) and showed preliminary predictive potential for subclinical kidney injury (AUC = 0.942; 95 % CI: 0.839–1.000, though the wide confidence interval and small sample size warrant cautious interpretation). In vitro, IAA activated the aryl hydrocarbon receptor (AhR) signaling pathway in HK-2 cells in a concentration-dependent manner, inducing oxidative stress, fibrosis, and apoptosis. These effects were reversed by the AhR antagonist CH-223,191 and recapitulated by the AhR agonist FICZ. CoCl₂-induced hypoxia synergistically augmented IAA-induced AhR pathway activation and cytotoxicity. Public transcriptomic analyses further showed AHR and CYP1B1 upregulation in chronic kidney disease (CKD) and diabetic kidney disease (DKD) kidney tissues, with significant positive correlations between HIF1A and AHR expression. Collectively, these preliminary findings suggest a potential association linking high-altitude hypoxia, elevated IAA, AhR activation, and kidney injury, but due to the limited sample size, they should be interpreted as hypothesis-generating and require validation in larger independent cohorts.