Distal renal tubular system-on-a-chip for studying the pathogenesis of influenza A virus-induced kidney injury

Influenza A viruses typically cause acute respiratory infections in humans. However, virus-induced acute kidney injury (AKI) has dramatically increased mortality. The pathogenesis remains poorly understood due to limited disease models. Here, a distal renal tubular system-on-a-chip (dRTSC) was constructed to explore the pathogenesis. The renal tubule-vascular reabsorption interface was recapitulated by co-culturing the distal renal tubule and peritubular vessel with a collagen-coated porous membrane. To study the pathways of influenza virus entry into the kidney, dynamic tracking of fluorescence-labeled virus-infected blood vessels was performed. For the first time, the virus was shown to enter the kidney rapidly by cell-free transmission without disrupting the vascular barrier. Direct virus infection of renal tubules in dRTSC reveals disruption of tight junctions, microvilli formation, polar distribution of ion transporters, and sodium reabsorption function. This robust platform allows for a straightforward investigation of virus-induced AKI pathogenesis. The combination with single-virus tracking technology provides new insights into understanding influenza virus-induced extra-respiratory disease.