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Platinum-induced kidney damage: Unraveling the DNA damage response (DDR) of renal tubular epithelial and glomerular endothelial cells following platinum injury


Krüger, Katharina; Thomale, Jürgen; Stojanović, Nikolina; Osmak, Maja; Henninger, Christian; Bormann, Stefanie; Fritz, Gerhard
Platinum-induced kidney damage: Unraveling the DNA damage response (DDR) of renal tubular epithelial and glomerular endothelial cells following platinum injury // Biochimica et biophysica acta-molecular cell research, 1853 (2015), 3; 685-698 doi:10.1016/j.bbamcr.2014.12.033 (međunarodna recenzija, članak, znanstveni)


Naslov
Platinum-induced kidney damage: Unraveling the DNA damage response (DDR) of renal tubular epithelial and glomerular endothelial cells following platinum injury

Autori
Krüger, Katharina ; Thomale, Jürgen ; Stojanović, Nikolina ; Osmak, Maja ; Henninger, Christian ; Bormann, Stefanie ; Fritz, Gerhard

Izvornik
Biochimica et biophysica acta-molecular cell research (0167-4889) 1853 (2015), 3; 685-698

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Platinating anticancer drugs; normal tissue damage; nephrotoxicity; DNA damage response

Sažetak
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. We comparatively investigated the stress responses of rat kidney tubular (NRK-52E) and glomerular cells (RGE) following treatmentwith 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. CisPt reduced the viability of tubular NRK-52E and glomerular RGE cells most efficiently. Cytotoxicity evoked by CarboPt occurredwith a delay, whichmight 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. 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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija



POVEZANOST RADA


Projekt / tema
098-0982913-2748 - Stanični odgovor na citotoksične spojeve i razvoj otpornosti (Maja Osmak, )
098-0982913-2850 - Povećanje transdukcije adenovirusnih vektora i otpornost stanica na citostatike (Andreja Ambriović Ristov, )

Ustanove
Institut "Ruđer Bošković", Zagreb

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus


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