Human kidney organoids model of Esculentoside A nephrotoxicity to investigate the role of epithelial-mesenchymal transition via STING signaling

Radix Phytolaccae (RP) has a long medicinal history and is commonly used to treat systemic edema and ascites in Asia. Although RP is known to cause nephrotoxicity, the role of its main constituent, Esculentoside A (EsA), in nephrotoxicity remains undetermined. We used kidney organoids derived from human inducible pluripotent stem cells (iPSCs) to model EsA nephrotoxicity accurately. Kidney organoids were differentiated and treated with EsA at doses of 0, 15, 30, or 60 μM for 48 h. The in vitro model was compared to a mouse model of EsA nephrotoxicity (intraperitoneally injected, 25 mg·kg-1). The mechanisms were investigated. Cell viability decreased dose-dependently after treatment with EsA. As polarity was lost, tubular cells decreased, similar to mouse EsA nephrotoxicity with upregulated vimentin expression and a stimulator of the interferon gene (STING). Furthermore, 60 μM EsA could induce endothelial inflammation, lead to mitochondrial damage and activate STING by translocating mtDNA into the cytoplasm to develop an inflammatory cascade and destroy renal endothelial cells with interstitial changes. The data suggest that kidney organoids derived from iPSCs are promising for investigating nephrotoxicity. EsA nephrotoxicity involves the epithelial-mesenchymal transition via STING signaling.