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Redox Biol. 2019 Jun 5;26:101234. doi: 10.1016/j.redox.2019.101234. [Epub ahead of print]

Tubular NOX4 expression decreases in chronic kidney disease but does not modify fibrosis evolution.

Author information

1
Laboratory of Nephrology, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Service of Nephrology, Department of Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.
2
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
3
Service of Clinical Pathology, Department of Pathology and Immunology, University Hospital and University of Geneva, Geneva, Switzerland.
4
Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5
Universität Innsbruck, Research Institute for Biomedical Aging Research, Rennweg 10, Innsbruck, Austria.
6
Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany.
7
Laboratory of Nephrology, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Service of Nephrology, Department of Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland. Electronic address: Sophie.deseigneux@hcuge.ch.

Abstract

BACKGROUND:

NADPH oxidase 4 (NOX4) catalyzes the formation of hydrogen peroxide (H2O2). NOX4 is highly expressed in the kidney, but its role in renal injury is unclear and may depend on its specific tissue localization.

METHODS:

We performed immunostaining with a specific anti-NOX4 antibody and measured NOX4 mRNA expression in human renal biopsies encompassing diverse renal diseases. We generated transgenic mice specifically overexpressing mouse Nox4 in renal tubular cells and subjected the animals to the unilateral ureteral obstruction (UUO) model of fibrosis.

RESULTS:

In normal human kidney, NOX4 protein expression was at its highest on the basolateral side of proximal tubular cells. NOX4 expression increased in mesangial cells and podocytes in proliferative diabetic nephropathy. In tubular cells, NOX4 protein expression decreased in all types of chronic renal disease studied. This finding was substantiated by decreased NOX4 mRNA expression in the tubulo-interstitial compartment in a repository of 175 human renal biopsies. Overexpression of tubular NOX4 in mice resulted in enhanced renal production of H2O2, increased NRF2 protein expression and decreased glomerular filtration, likely via stimulation of the tubulo-glomerular feedback. Tubular NOX4 overexpression had no obvious impact on kidney morphology, apoptosis, or fibrosis at baseline. Under acute and chronic tubular injury induced by UUO, overexpression of NOX4 in tubular cells did not modify the course of the disease.

CONCLUSIONS:

NOX4 expression was decreased in tubular cells in all types of CKD tested. Tubular NOX4 overexpression did not induce injury in the kidney, and neither modified microvascularization, nor kidney structural lesions in fibrosis.

KEYWORDS:

Chronic kidney disease; Diabetes; IgA nephropathy; Kidney fibrosis; NOX4; Renal biopsy; Tubular cells

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