Kidney Week

Abstract: FR-PO370

Regulation and Role of NADPH Oxidase 4 in CKD

Session Information

• CKD: Mechanisms - II
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Authors

• De Seigneux, Sophie M., University of Geneva, Geneva, Switzerland

Sophie M. De Seigneux,



• Rajaram, Renuga Devi, University of Geneva, Geneva, Switzerland

Renuga Devi Rajaram,



• Faivre, Anna, University of Geneva, Geneva, Switzerland

Anna Faivre,



• Delitsikou, Vasiliki, University of Geneva, Geneva, Switzerland

Vasiliki Delitsikou,



• Jaquet, Vincent, University of Geneva, Geneva, Switzerland

Vincent Jaquet,



• Lindenmeyer, Maja, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Maja Lindenmeyer,



• Cohen, Clemens D., Klinikum Munchen, Munchen, Germany

Clemens D. Cohen,

Background

While low-levels of reactive oxygen species (ROS) are important for physiological signaling, excessive ROS production has been implicated in CKD progression. Therefore, understanding the contribution of renal redox signaling in physiological and pathological context is essential to develop new therapeutics. NADPH oxidase 4 (NOX4) catalyzes the formation of hydrogen peroxide (H₂O₂). NOX4 is highly expressed in the kidney, but its role in renal damage 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 acute and chronic 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 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 176 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.

Conclusion

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.