Functional approaches to study renal and mitochondrial toxicity in vitro
Abstract
Nephrotoxicity is a common adverse effect of drugs that accounts for a substantial part of drug development discontinuations and market withdrawals. Within the kidney, the renal proximal tubule epithelial cells (RPTEC) are commonly affected by drug-induced nephrotoxicity, which is mainly due to their prominent role in secretion of xenobiotics. These transport processes not only result in high toxin exposures but also imply high energy metabolic rates, portrayed by a high mitochondrial density in these cells. Indeed, nephrotoxins are often substrates for renal secretory transporters and frequently interfere with mitochondrial functions. Unfortunately, nephrotoxicity of drug candidates is rarely detected during the preclinical development, which is attributed to the poor predictivity of animal experiments on the one hand and, on the other hand, the lack of predictive human in vitro test systems. The latter is mainly because most established RPTEC cell lines lost the characteristic expression of xenobiotic transporters rendering these cells unsuitable for sensitive nephrotoxicity detection. However, more recently presented cell lines including the RPTEC/TERT1 cells promise maintained functionality and polarization. Therefore, the work presented in this thesis describes the usability of the RPTEC/TERT1 cell line for in vitro nephrotoxicity testing. The key functionalities of the proximal tubule epithelium, reabsorption of water and secretion of cationic xenobiotics were…
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Evidence Hub reads this as a thesis, done in animal and cell cultures (in vitro), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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