Lenvatinib induces diarrhea in rats by promoting intestinal barrier injury via targeting AQP4

Abstract

Our study evaluated whether lenvatinib induces the disease process of diarrhea by facilitating intestinal epithelial barrier damage. Sprague-Dawley rats were orally administrated with 0.2 or 2 mg/kg lenvatinib for six consecutive days to induce diarrhea models. The diarrhea rate was monitored every day, and rats were sacrificed on day 6. We found that rats began to develop diarrhea on day 3 after lenvatinib treatment. Almost all rats treated with lenvatinib (2 mg/kg) developed grade 3 diarrhea. Intestinal villi structure damage and obvious inflammatory cell infiltration were observed in the colon tissues of lenvatinib-administrated rats. Lenvatinib significantly upregulated serum contents of intestinal injury biomarkers (D-lactate and DAO) but downregulated colon levels of tight junction proteins (ZO-1, Occludin, and Claudin-1) in rats. In vitro results showed that lenvatinib higher than 5 μM significantly attenuated the viability of human intestinal epithelial cell line Caco-2. Lenvatinib suppressed ZO-1, Occludin, and Claudin-1 levels, decreased the transepithelial electrical resistance value, and elevated paracellular permeability in Caco-2 cells. Mechanically, lenvatinib targeted AQP4 and inhibited its expression. Overexpressing AQP4 reversed lenvatinib-induced intestinal epithelial barrier injury in Caco-2 cells by inhibiting the MLCK/p-MLC2 signaling pathway. Collectively, lenvatinib triggers diarrhea by disrupting the intestinal barrier through downregulating AQP4 and activating the MLCK/p-MLC2 signaling pathway.