Extracellular Inorganic Phosphate-Induced Release of Reactive Oxygen Species: Roles in Physiological Processes and Disease Development

Abstract

Inorganic phosphate (Pi) is an essential nutrient for living organisms and is maintained in equilibrium in the range of 0.8-1.4 mM Pi. Pi is a source of organic constituents for DNA, RNA, and phospholipids and is essential for ATP formation mainly through energy metabolism or cellular signalling modulators. In mitochondria isolated from the brain, liver, and heart, Pi has been shown to induce mitochondrial reactive oxygen species (ROS) release. Therefore, the purpose of this review article was to gather relevant experimental records of the production of Pi-induced reactive species, mainly ROS, to examine their essential roles in physiological processes, such as the development of bone and cartilage and the development of diseases, such as cardiovascular disease, diabetes, muscle atrophy, and male reproductive system impairment. Interestingly, in the presence of different antioxidants or inhibitors of cytoplasmic and mitochondrial Pi transporters, Pi-induced ROS production can be reversed and may be a possible pharmacological target.

Keywords: hyperphosphataemia; inorganic phosphate; reactive oxygen species.

Figure 1

Phosphate-induced osteoblast apoptosis mediated by ROS production. In the localized remodelling area, when osteoblasts are exposed to Pi levels substantially more significant than those typically found in serum, osteoblasts initiate apoptotic pathways by uncontrolled ALP activity. Sodium-dependent Pi transporters internalize Pi. Pi promotes a hyperpolarization of the mitochondrial membrane potential (∆Ψm) until 2 h and induces ROS production. ROS can activate caspases. Ca²⁺ can be internalized by Ca²⁺ channels (although this calcium channel has little effect on Pi-induced osteoblast apoptosis signalling). High intracellular Ca²⁺ is observed after 4 h by Pi treatment, and Ca²⁺ may influence Pi-mediated bone cell apoptosis [19,22,23,24]. Solid black arrows indicate activation, and dashed black arrows indicate possible activation.

Figure 2

Phosphate-induced chondrocyte apoptosis is mediated by ROS production. In the growth bone plate, the cells terminally differentiated before zone calcification undergo apoptosis or programmed cell death. An increase in Pi levels is noted [25,26]. Sodium-dependent Pi transporters internalize Pi. Pi promotes a hyperpolarization of the mitochondrial membrane, which induces the production of ROS. ROS can activate caspases or death receptors and thus promote apoptosis, including DNA fragmentation [28,29,30,31]. Solid black arrows indicate activation.

Figure 3

High phosphate induces ROS production and impairs insulin secretion. It has been demonstrated that decreased insulin content and secretion are correlated under hyperphosphataemic states (elevated plasma Pi concentrations). Elevated extracellular Pi (1–5 mM) increases the mitochondrial membrane potential (∆Ψm), superoxide generation, caspase activation, and cell death [56]. Elevated extracellular Pi diminishes ATP synthesis, cytosolic Ca²⁺ oscillations, and insulin content and secretion in INS-1E cells and dispersed islet cells [56]. In addition, Pi-induced superoxide production promotes endoplasmic reticulum (ER) stress, which decreases insulin content, impairing insulin release [57]. Solid black arrows indicate activation. Solid red traces indicate inhibition.

Figure 4

High Pi impairs testicular function by oxidative stress. A high Pi diet, chronic kidney disease (CKD), or both in WKY rats [60] or C57BL/6 mice [59] increases serum Pi, oxidative stress, and apoptosis in the testicles. Testicular apoptosis induced by oxidative stress promotes a decrease in testicular weight, sperm count, sperm motilities, and seminiferous tubule diameter [59,60]. Nevertheless, this effect is restored by supplementation with a potent oxidative species scavenger, N-acetylcysteine (NAC) [59].

Figure 5

Oxidative stress high Pi-induced regulates physiological processes and disease development. High Pi level can induce oxidative stress and regulates bone remodeling [22,23,24], bone growth by endochondral ossification [28,29,30,31], cardiovascular diseases by atherosclerosis [40,41,42,43,44,45,46], type 2 diabetes [56,57], skeletal muscle atrophy [61] and male reproductive system dysfunction [59,60].