MO286: MIR-155 Deficiency Protects Renal Tubular Epithelial Cells from Telomeres and Genomic DNA Damage in Cisplatin-Induced Acute Kidney Injury

Abstract

Abstract BACKGROUND AND AIMS Cisplatin nephrotoxicity is an important cause of acute kidney injury (AKI), limiting cisplatin application in cancer therapy. Growing evidence had suggested that genome instability, telomere dysfunction and DNA damage were involved in the tubular epithelial cells (TECs) damage in cisplatin-induced AKI (cAKI). However, the exact mechanism is largely unknown. METHOD We subjected miR-155-/- mice and wild-type controls, as well as human proximal tubule cells, to cisplatin-induced AKI models. We assessed kidney function and injury with standard techniques and measured telomere by the fluorescence in situ hybridization. RESULTS Our study demonstrated that miR-155 deficiency significantly improved renal function and attenuated pathological damage and mortality during cAKI. Furthermore, miR-155 inhibition reduced cisplatin-induced TECs apoptosis, genome instability, telomere dysfunction and DNA damage both in vivo and in vitro. The miR-155 inhibition mediated protective effects may be caused by increasing expression of telomere repeat binding factor 1 (TRF1) and cyclin-dependent kinase 12 (CDK12), thereby limiting the telomere dysfunction and the genome DNA damage in cAKI. CONCLUSION We demonstrated that inhibition of miR-155 ameliorates AKI involving the targeting and regulation of TRF1 and CDK12, indicating a novel regulatory mechanism and elucidating a potential target for cisplatin-induced AKI treatment.