Transporter-dependent cytotoxicity of antiviral drugs in primary cultures of human proximal tubular cells

A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization–Dependent Cisplatin Toxicity

“…Kidney in vitro models are valuable tools for preclinical investigation of drug-induced toxicity, but inherently suffer from partial dedifferentiation (Lash et al, 2006;Brown et al, 2008;Lash et al, 2008). This reduces tight junction expression and epithelial barrier function, and limits replication of cell polarization-dependent drug-induced toxicity (Lash et al, 2018). By recapitulating the microenvironment of the physiological proximal tubule, recently developed kidney-on-a-chip models, also known as kidney microphysiological This article has not been copyedited and formatted.…”

Unexpected Enhancement of Cytotoxicity of Cisplatin in a Rat Kidney Proximal Tubular Cell Line Overexpressing Mitochondrial Glutathione Transport Activity

“…Our rationale for choosing the concentrations to which the NRK-52E cells were exposed was three-fold. First, plasma levels of CDDP in patients on a chemotherapy regimen with CDDP have been reported to be between 1.9 and 11 µM [62][63][64][65][66]. Second, studies of ours in primary cultures of human proximal tubular cells found that a concentration of 20 µM CDDP exhibited little or no cytotoxicity whereas a concentration of 90 µM CDDP was moderately cytotoxic [66].…”

Mapping Adverse Outcome Pathways for Kidney Injury as a Basis for the Development of Mechanism-Based Animal-Sparing Approaches to Assessment of Nephrotoxicity

“…It needs to be emphasized, however, that uptake of tenofovir into cells was not verified in this study, either by directly measuring intracellular levels of tenofovir or by characterization of cells with regard to expression of relevant drug transporters. Considering that tenofovir toxicity depends on transporters that mediate cellular uptake ( Uwai et al, 2007 ; Zhang et al, 2015 ; Lash et al, 2018 ), it is questionable if sufficiently high intracellular concentrations to inhibit Pol γ and block mtDNA replication were achieved in this model.…”

“…While the sequence of molecular events leading to ANP associated nephrotoxicity appears to present a universal mechanism by which nucleos(t)ide analogs may cause toxicity in a wide range of organs and tissues, including liver, heart, muscle and the nervous system ( Lewis and Dalakas, 1995 ; Lewis et al, 2003 ; Fontana, 2009 ; Fung et al, 2014 ), the particular susceptibility of the kidney, respectively the proximal tubule, to ANP toxicity is a result of transporter-mediated uptake into proximal tubule cells, leading to intracellular accumulation of ANPs. Organic anion transporter 1 (OAT1) and to a lesser extent organic anion transporter 3 (OAT3) located at the basolateral membrane of proximal tubule cells are recognized as the major membrane carriers for uptake of ANPs ( Figure 2 ) ( Uwai et al, 2007 ; Zhang et al, 2015 ; Lash et al, 2018 ). In support of this, inhibition of basolateral membrane transporters has been shown to reduce ANP nephrotoxicity ( Lalezari et al, 1995 ).…”

“…In support of this, inhibition of basolateral membrane transporters has been shown to reduce ANP nephrotoxicity ( Lalezari et al, 1995 ). In addition, recent data demonstrate ANP uptake into primary human kidney cells via apical carriers, potentially OAT4 or organic anion-transporting polypeptides (OATPs) ( Lash et al, 2018 ). Thus, the tissue-specificity of ANP toxicity appears to be determined predominantly by toxicokinetics and renal handling of these drugs.…”