Application of microfluidic perfusion culture for assessment of colistin nephrotoxicity

초록

Recent microfluidic perfusion culture system provides a more physiological disease model and enables various evaluations. Colistin nephrotoxicity is of growing concern due to its high incidence and the increased use of colistin, but preventive and therapeutic options are lacking. Here, we compared the relative nephrotoxicity of different colistin dosing regimens, and assessed the effects of dipeptidyl peptidase W inhibitors (DPP4i), as promising renoprotective agents, on colistin nephrotoxicity in a microfluidic culture device. We treated kidney tubular epithelial cells with colistin under physiological shear stress in bolus-simulating and continuous infusions over a 48 hour period. Evogliptin, a recently developed DPP4i, was administered into the lower channel to examine its renoprotective effects. We assessed cell viability, tight junction protein expression, transmembrane permeability, and kidney injury molecule-1 (KIM-1) levels for each group. The continuous infusion regimen resulted in significantly increased cell death, decreased zonula occludens-1 and occludin expression, higher transmembrane permeability, and higher KIM-1 levels compared with bolus-simulating regimen. The DPP4i decreased transmembrane permeability, but there was no difference in cell viability and KIM-1 levels. Overall, the bolus-simulating regimens showed lower cytotoxicity and preserved barrier integrity better than the continuous infusion regimen, and DPP4i might mitigate colistin-dependent transmembrane permeability.

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