NADPH oxidases, reactive oxygen species, and the kidney: friend and foe

Abstract

Reactive oxygen species (ROS) play an important role in normal cellular physiology. They regulate different biologic processes such as cell defense, hormone synthesis and signaling, activation of G protein-coupled receptors, and ion channels and kinases/phosphatases. ROS are also important regulators of transcription factors and gene expression. On the other hand, in pathologic conditions, a surplus of ROS in tissue results in oxidative stress with various injurious consequences such as inflammation and fibrosis. NADPH oxidases are one of the many sources of ROS in biologic systems, and there are seven isoforms (Nox1-5, Duox1, Duox2). Nox4 is the predominant form in the kidney, although Nox2 is also expressed. Nox4 has been implicated in the basal production of ROS in the kidney and in pathologic conditions such as diabetic nephropathy and CKD; upregulation of Nox4 may be important in renal oxidative stress and kidney injury. Although there is growing evidence indicating the involvement of NADPH oxidase in renal pathology, there is a paucity of information on the role of NADPH oxidase in the regulation of normal renal function. Here we provide an update on the role of NADPH oxidases and ROS in renal physiology and pathology.

Figure 1.

Physiologic role of NADPH oxidase-derived ROS. Green arrows indicate activation, and red lines with blunted ends indicate inhibition. NoxS, renal NADPH oxidases; VEGF, vascular endothelial growth factor; HIF, hypoxia inducible factor; ER, endoplasmic reticulum; MCP-1, monocyte chemotactic protein-1; MAP kinase, mitogen activated protein kinase; JNK, c-Jun N-terminal kinase 1; ERK, extracellular signal-regulated kinases; P38, p38 kinase.

Figure 2.

The role of NADPH oxidase along the nephron. Green arrows indicate activation, red lines with blunted ends indicate inhibition, and black lines indicate the direction of reactions. TRPC6, transient receptor potentials calcium-permeable cation channels; Na⁺, sodium ions, K⁺, potassium ions; H⁺, hydrogen ions; Cl⁻, chloride ions; Ca²⁺, calcium ions.