Myeloid Cell-Derived Hypoxia-Inducible Factor Attenuates Inflammation in Unilateral Ureteral Obstruction-Induced Kidney Injury
- 15 May 2012
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 188 (10), 5106-5115
- https://doi.org/10.4049/jimmunol.1103377
Abstract
Renal fibrosis and inflammation are associated with hypoxia, and tissue pO2 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.Keywords
This publication has 75 references indexed in Scilit:
- The Ngal reporter mouse detects the response of the kidney to injury in real timeNature Medicine, 2011
- Macrophages and Immunologic Inflammation of the KidneySeminars in Nephrology, 2010
- The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia–reperfusion injuryKidney International, 2008
- Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase PathwayMolecular Cell, 2008
- NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1αNature, 2008
- FoxA1 Translates Epigenetic Signatures into Enhancer-Driven Lineage-Specific TranscriptionCell, 2008
- Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase InhibitionGastroenterology, 2008
- Deletion of the Developmentally Essential Gene ATR in Adult Mice Leads to Age-Related Phenotypes and Stem Cell LossCell Stem Cell, 2007
- Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activityProceedings of the National Academy of Sciences of the United States of America, 2006
- Monocyte and macrophage heterogeneityNature Reviews Immunology, 2005