title: Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers.
abstract: The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with "omics" data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. katja.matheis@boehringer-ingelheim.com
authors.forename: Katja A
authors.initials: KA
authors.lastname: Matheis
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Com
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Gautier
authors.forename: Nelson
authors.initials: N
authors.lastname: Guerreiro
authors.forename: Arnd
authors.initials: A
authors.lastname: Brandenburg
authors.forename: Hans
authors.initials: H
authors.lastname: Gmuender
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sposny
authors.forename: Philip
authors.initials: P
authors.lastname: Hewitt
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.forename: Olaf
authors.initials: O
authors.lastname: Boernsen
authors.forename: Bjoern
authors.initials: B
authors.lastname: Riefke
authors.forename: Dana
authors.initials: D
authors.lastname: Hoffmann
authors.forename: Angela
authors.initials: A
authors.lastname: Mally
authors.forename: Arno
authors.initials: A
authors.lastname: Kalkuhl
authors.forename: Laura
authors.initials: L
authors.lastname: Suter
authors.forename: Frank
authors.initials: F
authors.lastname: Dieterle
authors.forename: Frank
authors.initials: F
authors.lastname: Staedtler
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D003524:Cyclosporins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods*; D005819:Genetic Markers / Q000235:genetics*; D005839:Gentamicins / Q000633:toxicity*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D003524:Cyclosporins; D005819:Genetic Markers; D005839:Gentamicins; C082770:IMM 125