Elevated plasma levels of the uremic toxin indoxyl sulfate positively correlates with plasma arsenic levels in acute promyelocytic leukemia patients: Evidence of renal AQP7 suppression mediated by the aryl hydrocarbon receptor

This study investigated the effects of indoxyl sulfate (IS), an endogenous metabolite and uremic toxin, on arsenic trioxide pharmacokinetics in acute promyelocytic leukemia patients with varying renal function. Plasma IS levels demonstrated a significant positive correlation with monomethylarsonic acid and dimethylarsinic acid concentrations in patients (P < .0001). In adenine-induced renally impaired rats, IS similarly correlated with elevated plasma inorganic arsenic (iAs), monomethylarsonic acid, and dimethylarsinic acid levels. Protein expression analysis indicated a downregulation of renal aquaporin (AQP) 7 and AQP3. In vitro studies confirmed that IS selectively inhibits AQP7 expression (62.1% reduction at 100 μM) through aryl hydrocarbon receptor activation in human embryonic kidney 293T cells, while AQP3 remained unaffected. Collectively, IS increases plasma arsenic concentration in renally impaired acute promyelocytic leukemia patients via aryl hydrocarbon receptor-mediated suppression of renal AQP7. SIGNIFICANCE STATEMENT: This study reveals that indoxyl sulfate inhibits renal aquaporin 7 via aryl hydrocarbon receptor activation, increasing plasma arsenic in arsenic trioxide-treated acute promyelocytic leukemia patients with renal impairment. As the first demonstration of this mechanism, to our knowledge, it provides crucial insights for optimizing therapy and reducing toxicity risks.