Scientific Publications by FDA Staff

Toxicol Sci 2014 Oct;141(2):484-92

MicroRNA-155 Deficient Mice Experience Heightened Kidney Toxicity when Dosed with Cisplatin.

Pellegrini KL, Han T, Bijol V, Saikumar J, Craciun FL, Chen WW, Fuscoe JC, Vaidya VS

The development of nephrotoxicity limits the maximum achievable dosage and treatment intervals for cisplatin chemotherapy. Therefore, identifying mechanisms that regulate this toxicity could offer novel methods to optimize cisplatin delivery. MicroRNAs are capable of regulating many different genes, and can influence diverse cellular processes, including cell death and apoptosis. We previously observed miR-155 to be highly increased following ischemic or toxic injury to the kidneys and, therefore, sought to determine whether mice deficient in miR-155 would respond differently to kidney injury. We treated C57BL/6 and miR-155-/- mice with 20 mg/kg of cisplatin and found a significantly higher level of kidney injury in the miR-155-/- mice. Genome-wide expression profiling and bioinformatic analysis indicated the activation of a number of canonical signaling pathways relating to apoptosis and oxidative stress over the course of the injury, and identified potential upstream regulators of these effects. One predicted upstream regulator was c-Fos, which has two confirmed miR-155 binding sites in its 3' UTR, and therefore, can be directly regulated by miR-155. We established that the miR-155-/- mice had significantly higher levels of c-Fos mRNA and protein than the C57BL/6 mice at 72 hours after cisplatin exposure. These data indicate a role for miR-155 in the cisplatin response and suggest that targeting of c-Fos could be investigated to reduce cisplatin-induced nephrotoxicity.