Oxidative stress: does it play a role in the genesis of essential hypertension and hypertension of uraemia?

Reactive oxygen species, including superoxide radicals, hydrogen peroxide, nitric oxide, peroxynitrite, hydroxyl radicals and hypochlorous acid are by-products of normal metabolic processes in cells. Reactive oxygen species can be found in several cells including macrophages and vascular smooth muscle cells. At low concentrations reactive oxygen species can act as physiological mediators of cellular responses whereas higher concentrations may cause cell damage [1,2]. The major sources of reactive oxygen species are leakages from the electron transport chains of mitochondria and endoplasmic reticulum. Cellular energy metabolism is based on the production of ATP through the electron transport reaction in which O2 accepts electrons andH þ and then is eventually reduced to water. Only 1–2% of the electrons are leaked to generate superoxide radicals in reactions mediated by coenzyme Q and ubiquinone and its complexes. During ageing (and probably in patients with hypertension and/or atherosclerosis) respiratory function declines and results in enhanced production of reactive oxygen species in mitochondria whereas the activities of free radical scavenging enzymes are reduced. In turn, reactive oxygen species induce stress responses by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell [3]. Neutrophils and macrophages produce reactive oxygen species during phagocytosis (‘oxygen burst’) or stimulation with several agents through the activation of nicotinamide adenine dinucleotide phosphate reduced [NAD(P)H] oxidase that is assembled at the plasma membrane from resident plasma membrane components and cytosolic protein components [4]. The NAD(P)H oxidase is also the major source of vascular superoxide production. Vascular NAD(P)H oxidase contains the plasma membrane components gp91phoxhomologues (nox1, nox4 or gp91phox) and p22phox, and the cytosolic protein components p47phox and p67phox [5]. It should be noted that the activation of vascular NAD(P)H oxidase by angiotensin II stimulates both superoxide production and NO production, thereby increasing peroxynitrite formation [6]. Endothelial nitric oxide synthase [7], inducible nitric oxide synthase [8] and xanthine oxidase [9] are other sources of superoxide radicals. After activation of vascular NAD(P)H oxidase (for example, by angiotensin II, thrombin, platelet-derived growth factor and others) the production of reactive oxygen species depends on activation of several intracellular signalling pathways including protein kinase C, the upstream activator of epidermal growth factor receptor, c-src, epidermal growth factor receptor transactivation, phosphatidylinositol-3-kinase and rac, a small molecular weight G protein. Several cellular signalling molecules such as protein tyrosine kinases, serine/threonine kinases, phospholipase C or cytosolic calcium are modified by reactive oxygen species. Reactive oxygen species activate protein tyrosine kinase pathways including epidermal growth factor receptor, insulin receptor, and platelet-derived-growth-factor receptor [10,11]. Reactive oxygen species activate extracellular signal-regulated kinases through c-src and ras [12]. Reactive oxygen species activate serine/threonine kinases including mitogen-activated protein kinase, p39 mitogen-activated protein kinase, Akt and protein kinase C [13,14].