title: Role of Nox4 in murine models of kidney disease.
abstract: Nox4 is a hydrogen peroxide-producing NADPH oxidase highly expressed in the kidney which has been linked to epithelial cell injury and diabetic-induced cellular dysfunction in cultured cells. The role of the enzyme for renal pathology in vivo, however, is unclear. To address this, three experimental animal models of renal injury (streptozotocin diabetes I, unilateral ureteral ligation (UUO), and 5/6 nephrectomy (5/6Nx)) were studied in either Nox4-inducible (Nox4(*/*)) or constitutive knockout (Nox4(-/-)) mice. Nox4 contributed more than 80% of diphenylene iodonium-sensitive H(2)O(2) formation of freshly isolated tubules determined by Amplex Red assay. In streptozotocin diabetes, acute deletion of Nox4 by tamoxifen-activated cre-recombinase increased albuminuria, whereas matrix deposition was similar between WT and Nox4(*/*) mice. Interestingly, renal Nox4 expression, mainly localized to tubular cells, decreased in the course of diabetes and this was not associated with a compensatory upregulation of Nox1 or Nox2. In the UUO model, renal expression of ICAM1, connective tissue growth factor, and fibronectin were higher in kidneys of Nox4(*/*) than control mice. Also in this model, levels of Nox4 decreased in the course of the disease. In the 5/6Nx model, which was performed in SV129 and SV129-Nox4(-/-) mice, no difference in the development of hypertension and albuminuria was found between the strains. Collectively, the first in vivo data of the kidney do not support the view that Nox4 is a main driver of renal disease. It rather appears that under specific conditions Nox4 may even slightly limit injury and disease progression.
authors: Institut für Kardiovaskuläre Physiologie, Goethe-Universität Frankfurt am Main, Germany.
authors: Andrea
authors: A
authors: Babelova
authors: Despina
authors: D
authors: Avaniadi
authors: Oliver
authors: O
authors: Jung
authors: Christian
authors: C
authors: Fork
authors: Janet
authors: J
authors: Beckmann
authors: Judith
authors: J
authors: Kosowski
authors: Norbert
authors: N
authors: Weissmann
authors: Narayana
authors: N
authors: Anilkumar
authors: Ajay M
authors: AM
authors: Shah
authors: Liliana
authors: L
authors: Schaefer
authors: Katrin
authors: K
authors: Schröder
authors: Ralf P
authors: RP
authors: Brandes
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000503:physiopathology / Q000652:urine; D000818:Animals; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000652:urine; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology / Q000652:urine; D004195:Disease Models, Animal; D005355:Fibrosis; D017353:Gene Deletion; D005919:Glomerular Filtration Rate; D006861:Hydrogen Peroxide / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009392:Nephrectomy; D051437:Renal Insufficiency / Q000378:metabolism / Q000503:physiopathology / Q000652:urine; D014517:Ureteral Obstruction / Q000378:metabolism / Q000503:physiopathology / Q000652:urine
chemical_list: C526318:CCN2 protein, mouse; C090509:Icam1 protein, mouse; D018799:Intercellular Adhesion Molecule-1; D055513:Connective Tissue Growth Factor; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse