title: Platinum-induced kidney damage: Unraveling the DNA damage response (DDR) of renal tubular epithelial and glomerular endothelial cells following platinum injury.
abstract: BACKGROUND
  Platinum compounds are potent anticancer drugs but also evoke considerable normal tissue damage. Here, we elucidate the molecular mechanisms contributing to the nephrotoxic effects of cisplatin.
  
  
  METHODS
  We comparatively investigated the stress responses of rat kidney tubular (NRK-52E) and glomerular cells (RGE) following treatment with cisplatin (CisPt), oxaliplatin (OxaliPt) and carboplatin (CarboPt). To this end, cell viability, apoptosis, cell cycle progression, DNA damage response (DDR) and repair of DNA adducts were investigated.
  
  
  RESULTS
  CisPt reduced the viability of tubular NRK-52E and glomerular RGE cells most efficiently. Cytotoxicity evoked by CarboPt occurred with a delay, which might be related to a retarded formation of Pt-(GpG) intrastrand crosslinks. RGE cells were more sensitive towards all platinum compounds than NRK-52E cells. Platinum drugs efficiently induced caspase-mediated apoptosis in tubular cells, while RGE cells favored G2/M arrest when treated with equitoxic platinum doses. Mitotic index of NKR-52E and RGE cells was worst affected by OxaliPt. Activation of the DDR was strikingly agent- and cell type-specific. Most comprehensive and substantial stimulation of DDR mechanisms was provoked by CisPt. Repair of Pt-(GpG) intrastrand crosslinks was best in RGE, which was reflected by high mRNA expression of nucleotide excision repair (NER) factors.
  
  
  CONCLUSIONS
  There are substantial differences regarding the cause of sensitivity and mechanisms of DDR between tubular and glomerular cells following platinum injury. CisPt is the most potent stimulator of the DDR. We hypothesize that specific DNA adducts and thereby forcefully activated pro-toxic DDR mechanisms contribute to the exceptionally high acute nephrotoxicity of CisPt.
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Krüger
authors.affiliation: Institute of Cell Biology, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.affiliation: Ruđer Bošković Institute, Division of Molecular Biology, 10000 Zagreb, Croatia.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Stojanović
authors.affiliation: Ruđer Bošković Institute, Division of Molecular Biology, 10000 Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Osmak
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Henninger
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bormann
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany. Electronic address: fritz@uni-duesseldorf.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin
keywords: DNA damage response; Nephrotoxicity; Normal tissue damage; Platinating anticancer drugs