Mechanism analysis of vancomycin-induced kidney injury focused on macrophages and circadian rhythm

<p>【Purpose】</p><p> Vancomycin(VCM) is a trump for the infection in a hospital. However, VCM has a huge clinical problem in that it causes acute kidney injury (AKI) frequently though, the detailed mechanism of developing VCM-induced AKI has not yet been elucidated. Circadian rhythms are observed in biological function, so administration focused on administration time suppresses side effects. Therefore, we carried out an analysis of whether circadian machinery influences VCM-induced AKI. </p><p></p><p>【Methods】</p><p> Each analysis uses the Uni-nephrectomized (UNx) mice and RAW264.7 cell, mice macrophage-like cells.</p><p></p><p>【Results and Conclusion】</p><p> The kidney function of UNx mice VCM-administered at 9 A.M. only decreased in intravenous administration at 9 A.M. or 9 P.M. To investigate the cause, an omics analysis of the kidney after VCM administration was conducted, as a result, the involvement of myeloid leukocytes was suggested. Then, when the cell population in the kidney was measured using flow cytometry, there was an administration time-dependent difference in the number of macrophages. Besides, depleting macrophages using liposomes including clodronate improved kidney function in administration at 9 A.M. After synchronizing clock gene expression by dexamethasone (DEX shock) in RAW264.7 cells, the cells were stimulated by VCM, and then inflammatory cytokines mRNA level was different depending on the elapsed time after DEX shock. Our study is expected to lead to the optimization of the therapy by VCM focused on circadian rhythms and the therapy for VCM-induced AKI targeting monocytes/macrophages. </p>