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- Title
TGF-β-mediated NADPH oxidase 4-dependent oxidative stress promotes colistin-induced acute kidney injury.
- Authors
Jeong, Bo Young; Park, Se-Ra; Cho, Sungkwon; Yu, Seong-Lan; Lee, Hoi Young; Park, Chang Gyo; Kang, Jaeku; Jung, Da-Young; Park, Moon Hyang; Hwang, Won-Min; Yun, Sung-Ro; Jung, Ju-Young; Yoon, Se-Hee
- Abstract
<bold>Background: </bold>Colistin (polymyxin E) is an important constituent of the polymyxin class of cationic polypeptide antibiotics. Intrarenal oxidative stress can contribute to colistin-induced nephrotoxicity. Nicotinamide adenine dinucleotide 3-phosphate oxidases (Noxs) are important sources of reactive oxygen species. Among the various types of Noxs, Nox4 is predominantly expressed in the kidney.<bold>Objectives: </bold>We investigated the role of Nox4 and benefit of Nox4 inhibition in colistin-induced acute kidney injury using in vivo and in vitro models.<bold>Methods: </bold>Human proximal tubular epithelial (HK-2) cells were treated with colistin with or without NOX4 knockdown, or GKT137831 (most specific Nox1/4 inhibitor). Effects of Nox4 inhibition on colistin-induced acute kidney injury model in Sprague-Dawley rats were examined.<bold>Results: </bold>Nox4 expression in HK-2 cells significantly increased following colistin exposure. SB4315432 (transforming growth factor-β1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells. Knockdown of NOX4 transcription reduced reactive oxygen species production, lowered the levels of pro-inflammatory markers (notably mitogen-activated protein kinases) implicated in colistin-induced nephrotoxicity and attenuated apoptosis by altering Bax and caspase 3/7 activity. Pretreatment with GKT137831 replicated these effects mediated by downregulation of mitogen-activated protein kinase activities. In a rat colistin-induced acute kidney injury model, administration of GKT137831 resulted in attenuated colistin-induced acute kidney injury as indicated by attenuated impairment of glomerulus function, preserved renal structures, reduced expression of 8-hydroxyguanosine and fewer apoptotic cells.<bold>Conclusions: </bold>Collectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.
- Subjects
REACTIVE oxygen species; ACUTE kidney failure; ANIMAL experimentation; APOPTOSIS; ENZYME inhibitors; EPITHELIAL cells; GENE expression; GLYCOSIDES; KIDNEY glomerulus; NEPHROTOXICOLOGY; NUCLEOSIDES; OXIDOREDUCTASES; PROTEIN kinases; RATS; TRANSFORMING growth factors-beta; OXIDATIVE stress; SIGNAL peptides; COLISTIN; IN vitro studies; IN vivo studies; PHARMACODYNAMICS
- Publication
Journal of Deaf Studies & Deaf Education, 2018, Vol 23, Issue 2, p962
- ISSN
1081-4159
- Publication type
journal article
- DOI
10.1093/jac/dkx479