Claudin17 deficient mice display leaky vasculature and organ injury accompanied by oxidative stress and inflammation

Abstract

The Multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood-tissue barrier regulation. Although CLDN17, a putative anion pore-forming CLDN, is assumed to regulate anion balance across the blood-tissue barriers, our knowledge about CLDN17 is limited. The current study investigated how Cldn17 deficiency in mice affects blood-tissue barrier integrity and vascular permeability. Cldn17−/− mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth until they turned 8-weeks. Adult Cldn17−/− mice displayed electrolyte imbalance, oxidative stress, increased vascular leakage, increased bone density, and organ injury. In addition, these mice demonstrated increased leukocytosis. A xenograft model to study pathological neovascularization showed higher vascular density in tumors developed in Cldn17−/− mice compared to wild-type controls. RNA-sequencing revealed hyperactivation of signaling pathways associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in blood-tissue barrier maintenance.