Amelioration of cisplatin-induced nephrotoxicity in peroxiredoxin I-deficient mice
- 522 Downloads
Cisplatin is one of the most potent chemotherapeutic agents used to treat cancer. However, cisplatin-induced nephrotoxicity, which is partly caused by oxidative damage, is a serious problem. We previously showed that murine embryonic fibroblasts deficient in Peroxiredoxin I (Prx I), a major Nrf2-linked anti-oxidant enzyme, are susceptible to cisplatin-induced cytotoxicity. In the present study, we examined the role of Prx I against cisplatin-induced renal injury in vivo using Prx I-null mice.
Prx I-null mice and wild-type (WT) mice were given an intraperitoneal injection of cisplatin, and tissues were removed and evaluated histopathologically. In addition, gene and protein expression of efflux transporters was analyzed.
In contrast to an in vitro cell study, Prx I-null mice exhibited less cisplatin-induced renal damage than WT mice in histological and blood biochemical analyses. Moreover, Prx I-null mice showed a higher clearance rate of cisplatin than WT mice following intraperitoneal cisplatin injection. Consistent with these results, Prx I-null mice exhibited higher expression of renal efflux transporters Mrp2 and Mrp4 compared with WT mice under both basal and the cisplatin-induced conditions. We suggest the enhanced transcriptional activity of c-Myc in Prx I-null mice may partly contribute the enhanced expression of renal efflux transporters.
In summary, the enhanced clearance rate of cisplatin significantly attenuates nephrotoxicity in Prx I-null mice.
KeywordsPeroxiredoxin I Cisplatin Nephrotoxicity Mrp c-Myc
Acute renal failure
Blood urea nitrogen
Multidrug resistance-associated protein
Nuclear factor-E2-related factor-2
Reactive oxygen species
The first two authors (K.O. and D.M.) contributed equally to this work. This research was supported by the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), and Grant-in-Aid for Challenging Exploratory Research (T.Y.). We would like to thank Prof. G.E, Mann whose comments and suggestions were of inestimable value for this study.
Conflict of interest
- 19.Okada K, Shoda J, Kano M, Suzuki S, Ohtake N, Yamamoto M, Takahashi H, Utsunomiya H, Oda K, Sato K, Watanabe A, Ishii T, Itoh K, Yokoi T, Yoshizato K, Sugiyama Y, Suzuki H (2007) Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers. Am J Physiol Gastrointest Liver Physiol 292:G1450–G1463PubMedCrossRefGoogle Scholar
- 20.Okada K, Shoda J, Taguchi K, Maher JM, Ishizaki K, Inoue Y, Ohtsuki M, Goto N, Takeda K, Utsunomiya H, Oda K, Warabi E, Ishii T, Osaka K, Hyodo I, Yamamoto M (2008) Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice. Am J Physiol Gastrointest Liver Physiol 295:G735–G747PubMedCrossRefGoogle Scholar
- 23.Royer B, Guardiola E, Polycarpe E, Hoizey G, Delroeux D, Combe M, Chaigneau L, Samain E, Chauffert B, Heyd B, Kantelip JP, Pivot X (2005) Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding. Anticancer Drugs 16:1009–1016PubMedCrossRefGoogle Scholar