title: p47(phox) contributes to albuminuria and kidney fibrosis in mice.
abstract: Reactive oxygen species (ROS) have an important pathogenic role in the development of many diseases, including kidney disease. Major ROS generators in the glomerulus of the kidney are the p47(phox)-containing NAPDH oxidases NOX1 and NOX2. The cytosolic p47(phox) subunit is a key regulator of the assembly and function of NOX1 and NOX2 and its expression and phosphorylation are upregulated in the course of renal injury, and have been shown to exacerbate diabetic nephropathy. However, its role in nondiabetic-mediated glomerular injury is unclear. To address this, we subjected p47(phox)-null mice to either adriamycin-mediated or partial renal ablation-mediated glomerular injury. Deletion of p47(phox) protected the mice from albuminuria and glomerulosclerosis in both injury models. Integrin α1-null mice develop more severe glomerulosclerosis compared with wild-type mice in response to glomerular injury mainly due to increased production of ROS. Interestingly, the protective effects of p47(phox) knockout were more profound in p47(phox)/integrin α1 double knockout mice. In vitro analysis of primary mesangial cells showed that deletion of p47(phox) led to reduced basal levels of superoxide and collagen IV production. Thus, p47(phox)-dependent NADPH oxidases are a major glomerular source of ROS, contribute to kidney injury, and are potential targets for antioxidant therapy in fibrotic disease.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Xiwu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Pathology, Immunology, and Microbiology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Paisit
authors.initials: P
authors.lastname: Paueksakon
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
authors.affiliation: 1] Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA [2] Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: 1] Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA [2] Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: 1] Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA [2] Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee, USA.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
mesh_terms: D000419:Albuminuria / Q000201:enzymology*; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D004317:Doxorubicin; D066246:ErbB Receptors / Q000378:metabolism; D039423:Integrin alpha1 / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009400:Nephrosclerosis / Q000201:enzymology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D039423:Integrin alpha1; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D020744:rac GTP-Binding Proteins