title: Hypoxia-inducible factor activation protects the kidney from gentamicin-induced acute injury.
abstract: Gentamicin nephrotoxicity is one of the most common causes of acute kidney injury (AKI). Hypoxia-inducible factor (HIF) is effective in protecting the kidney from ischemic and toxic injury. Increased expression of HIF-1α mRNA has been reported in rats with gentamicin-induced renal injury. We hypothesizd that we could study the role of HIF in gentamicin-induced AKI by modulating HIF activity. In this study, we investigated whether HIF activation had protective effects on gentamicin-induced renal tubule cell injury. Gentamicin-induced AKI was established in male Sprague-Dawley rats. Cobalt was continuously infused into the rats to activate HIF. HK-2 cells were pre-treated with cobalt or dimethyloxalylglycine (DMOG) to activate HIF and were then exposed to gentamicin. Cobalt or DMOG significantly increased HIF-1α expression in rat kidneys and HK-2 cells. In HK-2 cells, HIF inhibited gentamicin-induced reactive oxygen species (ROS) formation. HIF also protected these cells from apoptosis by reducing caspase-3 activity and the amount of cleaved caspase-3, and -9 proteins. Increased expression of HIF-1α reduced the number of gentamicin-induced apoptotic cells in rat kidneys and HK-2 cells. HIF activation improved the creatinine clearance and proteinuria in gentamicin-induced AKI. HIF activation also ameliorated the extent of histologic injury and reduced macrophage infiltration into the tubulointerstitium. In gentamicin-induced AKI, the activation of HIF by cobalt or DMOG attenuated renal dysfunction, proteinuria, and structural damage through a reduction of oxidative stress, inflammation, and apoptosis in renal tubular epithelial cells.
authors.affiliation: Department of Internal Medicine, Maryknoll Hospital, Busan, Korea.
authors.forename: Jeong-myung
authors.initials: JM
authors.lastname: Ahn
authors.forename: Sun Jin
authors.initials: SJ
authors.lastname: You
authors.forename: Yun-Mi
authors.initials: YM
authors.lastname: Lee
authors.forename: Se-Won
authors.initials: SW
authors.lastname: Oh
authors.forename: Shin-young
authors.initials: SY
authors.lastname: Ahn
authors.forename: Sejoong
authors.initials: S
authors.lastname: Kim
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Chin
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Chae
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Na
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism*; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D005839:Gentamicins / Q000633:toxicity*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D005839:Gentamicins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D003035:Cobalt; D053148:Caspase 3; D053453:Caspase 9; C040947:oxalylglycine