NADPH oxidase as a therapeutic target for oxalate induced injury in kidneys

Abstract

A major role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes is to catalyze the production of superoxides and other reactive oxygen species (ROS). These ROS, in turn, play a key role as messengers in cell signal transduction and cell cycling, but when they are produced in excess they can lead to oxidative stress (OS). Oxidative stress in the kidneys is now considered a major cause of renal injury and inflammation, giving rise to a variety of pathological disorders. In this review, we discuss the putative role of oxalate in producing oxidative stress via the production of reactive oxygen species by isoforms of NADPH oxidases expressed in different cellular locations of the kidneys. Most renal cells produce ROS, and recent data indicate a direct correlation between upregulated gene expressions of NADPH oxidase, ROS, and inflammation. Renal tissue expression of multiple NADPH oxidase isoforms most likely will impact the future use of different antioxidants and NADPH oxidase inhibitors to minimize OS and renal tissue injury in hyperoxaluria-induced kidney stone disease.

Figure 1

Production of ROS and different reactions. ROS with 1 free electron are shown in red and 2 free electrons are shown in blue. ROS, when produced in excess, cause damage to different components of the cell. Excess production of hydrogen peroxide (H₂O₂) and peroxynitrite (ONOO⁻) leads to the production of singlet oxygen (¹O₂). The other radicals shown in the figure are superoxide (•O₂ ⁻), nitric oxide (•NO), nitrogen dioxide (•NO₂), hydroxyl radical (•OH), glutathione (GSH), glutathione disulphide (GSSG), thiocyanate (SCN⁻), hypothiocyanous acid (HOSCN), hypochlorous acid (HOCl), and chroramine (R-NHCl). Figure modified from [1, 46].

Figure 2

Seven different NOX isoforms-NADPH oxidase complexes. NOX isoform expression is relatively regulated at different transcriptional, post-transcriptional and translational levels under certain pathophysiological conditions. Most of the NOX isoforms have structural similarities to NOX2, with maximum in NOX3. NOX4 is most abundant in the kidneys in various kinds of cells. NOX4 is known to be constitutively active and do not require any subunits. NOX5 is directly activated by calcium. The core subunits of all the complexes (NOX1-NOX5, DUOX1/DUOX2) are shown in blue; their membrane bound subunits (p22phox, DUOXA1 and DUOXA2) are shown in green; the cytosolic subunits which acts as organizers (p40phox, NOXO1 and p47phox) are shown in red; activator subunits of NADPH oxidase complexes present in the cytosol (p67phox and NOXA1) are shown in orange; small GTPases (RAC1 and RAC2) are shown in grey; EF hand motifs are shown in yellow which bind with calcium to regulate the activity of NOX5, DUOX1 and DUOX2 (see text for details).

Figure 3

Different isoforms of NADPH oxidase complex present in different parts of the kidneys. The Nox isoforms expressed in the cortex and medulla as shown in the nephron and different cellular populations in the glomerulus (see text for details).