Fluid shear stress stimulates MATE2-K expression via Nrf2 pathway activation.

Accurate prediction of drug-induced renal toxicity is necessary for development of safer drugs for patients. Cellular assay systems that recapitulate physiologically relevant microenvironments have been proposed for correct estimation of drug responses in the human body. However, establishment of such assay systems for accurate prediction of renal toxicity is challenging because of the lack of readily available in vitro assay systems. In this study, we investigated the cellular response to fluid shear stress, which is a characteristic of the environment in the kidney proximal tubules, using microfluidic devices. The global gene expression profiles of human primary proximal tubule cells under the fluidic conditions revealed upregulation of MATE2-K and activation of Nrf2 signaling in response to fluid shear stress. Network and cell biological analysis additionally showed that expression of MATE2-K is regulated by Nrf2 signaling. These results strongly suggest that fluid shear stress is involved in the expression and maintenance of function of tissue-specific drug transporters in the proximal tubule, where the cells are exposed to continuous shear stress by primary urine. Furthermore, the microfluidic culture of human proximal tubules was demonstrated to be a useful system to analyze the regulatory mechanisms of gene expression in physiologically relevant cell conditions.