Tubular NOX4 expression decreases in chronic kidney disease but does not modify fibrosis evolution
Renuga Devi Rajaram,
Romain Dissard,
Anna Faivre,
Frédérique Ino,
Vasiliki Delitsikou,
Vincent Jaquet,
Thomas Cagarelli,
Maja Lindenmeyer,
Pidder Jansen-Duerr,
Clemens Cohen,
Solange Moll,
Sophie de Seigneux
Affiliations
Renuga Devi Rajaram
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
Romain Dissard
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
Anna Faivre
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
Frédérique Ino
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
Vasiliki Delitsikou
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
Vincent Jaquet
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Thomas Cagarelli
Service of Clinical Pathology, Department of Pathology and Immunology, University Hospital and University of Geneva, Geneva, Switzerland
Maja Lindenmeyer
Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Pidder Jansen-Duerr
Universität Innsbruck, Research Institute for Biomedical Aging Research, Rennweg 10, Innsbruck, Austria
Clemens Cohen
Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany
Solange Moll
Service of Clinical Pathology, Department of Pathology and Immunology, University Hospital and University of Geneva, Geneva, Switzerland
Sophie de Seigneux
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; Corresponding author. Laboratory of Nephrology, University Hospital and University of Geneva, Department of Medicine Specialties, 1 rue Michel Servet 1211, Geneva 4, Switzerland.
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: NOX4, Tubular cells, Kidney fibrosis, Renal biopsy, Diabetes, IgA nephropathy, Chronic kidney disease
