Evaluation of rapid transepithelial electrical resistance (TEER) measurement as a metric of kidney toxicity in a high-throughput microfluidic culture system

• Published in: Scientific reports Vol. 12; no. 1; p. 13182
• Main Authors: Shaughnessey, Erin M., Kann, Samuel H., Azizgolshani, Hesham, Black, Lauren D., Charest, Joseph L., Vedula, Else M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/1435/2163; 631/61/2035; Apoptosis; Cell culture; Cell death; Cisplatin; Cytotoxicity; Drug dosages; Electrical resistivity; Fluid flow; High-throughput screening; Humanities and Social Sciences; Kidneys; L-Lactate dehydrogenase; Lactic acid; Mechanical stimuli; Microfluidics; Microvasculature; Morphology; multidisciplinary; Permeability; Phenotypes; Physiology; Questioning; Science; Science (multidisciplinary); Shear stress; Tissue culture; Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-16590-9

Rapid non-invasive kidney-specific readouts are essential to maximizing the potential of microfluidic tissue culture platforms for drug-induced nephrotoxicity screening. Transepithelial electrical resistance (TEER) is a well-established technique, but it has yet to be evaluated as a metric of toxicity in a kidney proximal tubule (PT) model that recapitulates the high permeability of the native tissue and is also suitable for high-throughput screening. We utilized the PREDICT96 high-throughput microfluidic platform, which has rapid TEER measurement capability and multi-flow control, to evaluate the utility of TEER sensing for detecting cisplatin-induced toxicity in a human primary PT model under both mono- and co-culture conditions as well as two levels of fluid shear stress (FSS). Changes in TEER of PT-microvascular co-cultures followed a dose-dependent trend similar to that demonstrated by lactate dehydrogenase (LDH) cytotoxicity assays and were well-correlated with tight junction coverage after cisplatin exposure. Additionally, cisplatin-induced changes in TEER were detectable prior to increases in cell death in co-cultures. PT mono-cultures had a less differentiated phenotype and were not conducive to toxicity monitoring with TEER. The results of this study demonstrate that TEER has potential as a rapid, early, and label-free indicator of toxicity in microfluidic PT-microvascular co-culture models.