{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T13:18:38Z","timestamp":1784380718925,"version":"3.55.0"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"6","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["DK60635"],"award-info":[{"award-number":["DK60635"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,22]]},"abstract":"<jats:p>\n                    In this investigation, a potentially novel signaling pathway in gentamicin-induced acute kidney injury\u2014worsened by overexpression of proximal tubular enzyme,\n                    <jats:italic>myo<\/jats:italic>\n                    -inositol oxygenase (MIOX)\u2014was elucidated. WT, MIOX-transgenic (MIOX-Tg), and MIOX-KO mice were used. Gentamicin was administered to induce tubular injury. MIOX-Tg mice had severe tubular lesions associated with increased serum creatinine and proteinuria. Lesions were relatively mild, with no rise in serum creatinine and no albuminuria in MIOX-KO mice. Transfection of HK-2 cells with MIOX-pcDNA led to increased gentamicin-induced reactive oxygen species (ROS). Marked increase of ROS-mediated lipid hydroperoxidation was noted in MIOX-Tg mice, as assessed by 4-HNE staining. This was associated with increased expression of arachidonate 12-lipoxygenase (ALOX-12) and generation of 12-hydroxyeicosatetraenoic acid (12-HETE). In addition, notable monocyte\/macrophage influx, upregulation of NF-\u03baB and inflammatory cytokines, and apoptosis was observed in MIOX-Tg mice. Treatment of cells with ALOX-12 siRNA abolished gentamicin-mediated induction of cytokines and 12-HETE generation. HETE-12 treatment promoted this effect, along with upregulation of various signaling kinases and activation of GPCR31. Similarly, treatment of cells or mice with the ALOX-12 inhibitor ML355 attenuated inflammatory response, kinase signaling cascade, and albuminuria. Collectively, these studies highlight a potentially novel mechanism (i.e., the ROS\/ALOX-12\/12-HETE\/GPR31 signaling axis) relevant to gentamicin-induced nephrotoxicity modulated by MIOX.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.155487","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T14:00:57Z","timestamp":1647871257000},"source":"Crossref","is-referenced-by-count":37,"title":["Modulation of gentamicin-induced acute kidney injury by myo-inositol oxygenase via the ROS\/ALOX-12\/12-HETE\/GPR31 signaling 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