miR-124/MCP-1 signaling pathway modulates the protective effect of itraconazole on acute kidney injury in a mouse model of disseminated candidiasis

Abstract

Previous studies have indicated that monocyte chemoattractant protein-1 (MCP-1), also referred to as C-C motif chemokine ligand 2, has a significant role in the pathogenesis of sepsis, however, how microRNAs (miRs) contribute to this process remains to be fully elucidated. In the present study, using a mouse model of disseminated candidiasis, the renoprotective effect of itraconazole (ITR) and adenovirus-delivered miR-124 was investigated. The mice were treated with ITR (50 mg/kg) or transfected with miR-124 mimics via tail-vein injection 7 days prior to Candida albicans infection. The survival outcome was monitored following candidiasis-induced sepsis with ITR or miR-124 mimics treatment. The levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6, were determined using enzyme-linked immunosorbent assays. The mRNA and protein levels were assayed using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The results showed that ITR and miR-124 mimics improved the survival outcome in candidiasis-induced septic mice. The findings also indicated a significant downregulation in the serum levels of TNF-α, IL-1β and IL-6 in the septic mice treated with ITR or miR-124 mimics. Of note, ITR treatment significantly increased the expression of miR-124 and decreased the levels of MCP-1 in the kidneys of the septic mice. It was also shown that the overexpression of miR-124 reduced the expression of MCP-1 and attenuated candidiasis-induced acute kidney injury (AKI) in septic mice. Transfection with miR-124 mimics was equivalent to ITR in reducing the excessive inflammatory response and renal lesions in septic mice. These results provided evidence supporting the use of miR-124 mimics as a therapeutic approach for attenuating candidiasis-induced AKI.