NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury

Article Article scientifique Article NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury eng 2012 author Nlandu Khodo Stellor 711566 author Dizin Eva author Sossauer Gaëtan 670555 author Szanto Ildiko 0000-0003-3566-7991 133688 author Martin Pierre-Yves 65591 author Feraille Eric 27356 author Krause Karl-Heinz 23022 author De Seigneux Matthey Sophie 105798 1967-1976 10.1681/ASN.2012040373 23100220 1046-6673 NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD(cl1)) cell line increased TGF-β1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1α and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions. Animals Antioxidants/metabolism Apoptosis Atrophy Capillaries/pathology Fibrosis Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Kidney/pathology Kidney Diseases/enzymology/genetics/pathology Male Membrane Glycoproteins/metabolism Mice Mice, Inbred C57BL Mice, Knockout NADPH Oxidase/metabolism NF-E2-Related Factor 2/metabolism Oxidative Stress Ureteral Obstruction Vascular Endothelial Growth Factor A/metabolism Dewey 612 Dewey 616 Dewey 616.07 134 Département de physiologie cellulaire et métabolisme 21C 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 38 Radicaux libres et cellules souches embryonnaires 60 465 Stress oxydatif et insuline 795 Journal of the American Society of Nephrology 23 12 9137fd33-06ca-430a-8388-9b0cff4581f0 Article (Published version) Restricted 1967.full.pdf 1796127 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

Title	Published in	Year	Views	Downloads

Role OF NADPH Oxidase 4 (NOX4) in the pathophysiology of kidney diseases		2014	1,035	984
NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury	Journal of the American Society of Nephrology	2012	561	0

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Nlandu Khodo, Stellor