Cisplatin Nephrotoxicity Is Induced via Poly(ADP-ribose) Polymerase Activation in Adult Zebrafish and Mice

Kim, M.J., Moon, D., Jung, S., Lee, J., Kim, J.
American journal of physiology. Regulatory, integrative and comparative physiology   318(5): R843-R854 (Journal)
Registered Authors
Kim, Myoung-Jin
cisplatin, poly(ADP-ribose) polymerase, proximal tubule, toxicity, zebrafish
MeSH Terms
  • Animals
  • Benzamides/pharmacology
  • Cisplatin*
  • DNA Damage
  • Disease Models, Animal
  • Kidney Diseases/chemically induced
  • Kidney Diseases/enzymology*
  • Kidney Diseases/pathology
  • Kidney Diseases/prevention & control
  • Kidney Tubules/drug effects
  • Kidney Tubules/enzymology*
  • Kidney Tubules/pathology
  • Male
  • Mice, Inbred C57BL
  • Phenanthrenes/pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
  • Poly(ADP-ribose) Polymerases/metabolism*
  • Signal Transduction
  • Zebrafish
  • Zebrafish Proteins/metabolism*
32186196 Full text @ Am. J. Physiol. Regul. Integr. Comp. Physiol.
Cisplatin is a well-known chemotherapy medication used to treat numerous cancers. However, treatment with cisplatin in cancer therapy has major side effects, such as nephrotoxic acute kidney injury. Adult vertebrate kidneys are commonly used as models of cisplatin-induced nephrotoxic acute kidney injury. Embryonic zebrafish kidney is more simplified and is composed simply of two nephrons and thus is an excellent model for the investigation of cisplatin nephrotoxicity. Here, we developed a novel model to induce cisplatin nephrotoxicity in adult zebrafish and demonstrated that intraperitoneal injection of cisplatin caused a decline in kidney proximal tubular function based on fluorescein-labeled dextran uptake and alkaline phosphatase staining. We also showed that cisplatin induced histological injury of the kidney tubules quantified by tubular injury scores on the periodic acid-Schiff-stained kidney sections. As shown in a mouse model of cisplatin-induced nephrotoxicity, the activation of poly(ADP-ribose) polymerase (PARP), an enzyme implicated in cisplatin-induced cell death, was markedly increased after cisplatin injection in adult zebrafish. Furthermore, pharmacological inhibition of PARP using specific PARP inhibitor PJ34 or 3-aminobenzamide ameliorated kidney proximal tubular functional and histological damages in cisplatin-injected adult zebrafish kidneys. Administration of a combination of PARP inhibitors PJ34 and 3-aminobenzamide additively protected renal function and histology in zebrafish and mouse models of cisplatin nephrotoxicity. In conclusion, these data suggest that adult zebrafish is not only suitable for drug screening and genetic manipulation, but also useful as a simplified but powerful model to study the pathophysiology of cisplatin nephrotoxicity and establish new therapies for treating human kidney diseases.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes