title: Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury.
abstract: Renal fibrosis and inflammation are associated with hypoxia, and tissue pO(2) plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney, they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established. To address this issue, we used Cre-loxP recombination to activate or to delete both Hif-1 and Hif-2 either globally or cell type specifically in myeloid cells. Global activation of Hif suppressed inflammation and fibrogenesis in mice subjected to unilateral ureteral obstruction, whereas activation of Hif in myeloid cells suppressed inflammation only. Suppression of inflammatory cell infiltration was associated with downregulation of CC chemokine receptors in renal macrophages. Conversely, global deletion or myeloid-specific inactivation of Hif promoted inflammation. Furthermore, prolonged hypoxia suppressed the expression of multiple inflammatory molecules in noninjured kidneys. Collectively, we provide experimental evidence that hypoxia and/or myeloid cell-specific HIF activation attenuates renal inflammation associated with chronic kidney injury.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Hanako
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Victoria
authors.initials: V
authors.lastname: Gilbert
authors.forename: Qingdu
authors.initials: Q
authors.lastname: Liu
authors.forename: Pinelopi P
authors.initials: PP
authors.lastname: Kapitsinou
authors.forename: Travis L
authors.initials: TL
authors.lastname: Unger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rha
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000502:physiology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D061251:Primary Cell Culture; D014517:Ureteral Obstruction / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse