TY - JOUR
T1 - Application of RPTEC/TERT1 cells for investigation of repeat dose nephrotoxicity
T2 - A transcriptomic study
AU - Aschauer, Lydia
AU - Limonciel, Alice
AU - Wilmes, Anja
AU - Stanzel, Sven
AU - Kopp-Schneider, Annette
AU - Hewitt, Philip
AU - Lukas, Arno
AU - Leonard, Martin
AU - Pfaller, Walter
AU - Jennings, Paul
N1 - Funding Information:
This project was funded by the European Union’s 7th Framework Programme ( FP7/2007–2013 ) under Grant agreement no 202222, Predict-IV.
PY - 2015/12/25
Y1 - 2015/12/25
N2 - The kidney is a major target organ for toxicity. Incidence of chronic kidney disease (CKD) is increasing at an alarming rate due to factors such as increasing population age and increased prevalence of heart disease and diabetes. There is a major effort ongoing to develop superior predictive models of renal injury and early renal biomarkers that can predict onset of CKD. In the EU FP7 funded project, Predict-IV, we investigated the human renal proximal tubule cells line, RPTEC/TERT1 for their applicability to long term nephrotoxic mechanistic studies. To this end, we used a tiered strategy to optimise dosing regimes for 9 nephrotoxins. Our final testing protocol utilised differentiated RPTEC/TERT1 cells cultured on filter inserts treated with compounds at both the apical and basolateral side, at concentrations not exceeding IC10, for 14 days in a 24 h repeat application. Transepithelial electrical resistance and supernatant lactate were measured over the duration of the experiments and genome wide transcriptomic profiles were assayed at day 1, 3 and 14. The effect of hypoxia was investigated for a subset of compounds. The transcriptomic data were analysed to investigate compound-specific effects, global responses and mechanistically informative signatures. In addition, several potential clinically useful renal injury biomarkers were identified.
AB - The kidney is a major target organ for toxicity. Incidence of chronic kidney disease (CKD) is increasing at an alarming rate due to factors such as increasing population age and increased prevalence of heart disease and diabetes. There is a major effort ongoing to develop superior predictive models of renal injury and early renal biomarkers that can predict onset of CKD. In the EU FP7 funded project, Predict-IV, we investigated the human renal proximal tubule cells line, RPTEC/TERT1 for their applicability to long term nephrotoxic mechanistic studies. To this end, we used a tiered strategy to optimise dosing regimes for 9 nephrotoxins. Our final testing protocol utilised differentiated RPTEC/TERT1 cells cultured on filter inserts treated with compounds at both the apical and basolateral side, at concentrations not exceeding IC10, for 14 days in a 24 h repeat application. Transepithelial electrical resistance and supernatant lactate were measured over the duration of the experiments and genome wide transcriptomic profiles were assayed at day 1, 3 and 14. The effect of hypoxia was investigated for a subset of compounds. The transcriptomic data were analysed to investigate compound-specific effects, global responses and mechanistically informative signatures. In addition, several potential clinically useful renal injury biomarkers were identified.
KW - Nephrotoxin
KW - Proximal tubule
KW - RPTEC/TERT1
KW - Stress response
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=84919625742&partnerID=8YFLogxK
U2 - 10.1016/j.tiv.2014.10.005
DO - 10.1016/j.tiv.2014.10.005
M3 - Article
C2 - 25450743
AN - SCOPUS:84919625742
SN - 0887-2333
VL - 30
SP - 106
EP - 116
JO - Toxicology in Vitro
JF - Toxicology in Vitro
IS - 1
ER -
