Linking Oxidative Stress, the Renin-Angiotensin System, and Hypertension

Abstract

See related article, pp 452-459T he involvement of oxidative stress in hypertension and in renal and cardiovascular diseases has been intensely studied since the early 1990s. Oxidative stress has been implicated in chronic kidney disease, 1 endothelial damage, atherosclerosis, 2 and myocardial disease, 3 whereas the administration of antioxidants, such as Tempol 4 and N-acetyl cysteine, 1 has been shown to exert a protective effect against these conditions. Nevertheless, the molecular mechanisms and intracellular pathways involved in the pathogenic effects of oxidative stress are still far from established.Several studies suggest that one of the mechanisms linking oxidative stress and hypertension is represented by activation of the renin-angiotensin-aldosterone system (RAAS). 5 The relationship between the RAAS and the pathogenesis of hypertension is well known. Activation of the RAAS takes place through the angiotensin (Ang) II type 1 (AT 1 ) receptor, which promotes renal and systemic vasoconstriction and enhances tubular sodium reabsorption directly at the proximal tubule and indirectly through the action of aldosterone at the distal nephron. These actions minimize contraction of the extracellular volume and hypotension in a context of fluid loss and dehydration but may lead to the development of hypertension when set in motion under pathophysiologic conditions.A number of recent observations have revealed a very close relationship between oxidative stress and RAAS overactivation. In vitro experiments have shown that Ang II stimulates mesangial cells to produce superoxide anions, 6 whereas inhibition of the RAAS was shown to diminish oxidative stress in several pathological conditions. 7 In addition, the nuclear factor-B transcription factor, a key player in inflammation, can be activated by either oxidative stress or binding of Ang II to the AT 1 receptor, 8 further suggesting the existence of a link between these processes.Recent studies by Banday and Lokhandwala 9 contributed to extend our knowledge of the intracellular mechanisms by which oxidative stress and the RAAS can interact to promote sustained blood pressure elevation. In the first of these studies, these investigators showed that rats treated chronically with L-buthionine sulfoximine (BSO), an oxidant agent, developed hypertension and showed increased abundance of the AT 1 receptor at the proximal tubules. Moreover, Ang II binding to the AT 1 receptor not only was enhanced in BSO-treated rats but also evoked more intense activation of phospholipase C and intracellular accumulation of inositol triphosphate. Most interestingly, activation of AT 1 -mediated mitogen-activated protein kinase, Na-KATPase, and Na/H exchanger 3 (NHE3) was enhanced in proximal tubular cells of rats that had been pretreated with BSO. These observations suggested that oxidative stress sensitized proximal tubular cells to the effects of Ang II, exacerbating the sodiumretaining effect evoked by the peptide. Because the expression of the AT 1 receptor itself was also increase...

Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II

“…Collectively, these data support our hypothesis that increased RAAS activity in hypertension exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation by inducing oxidative stress in the muscle. Increased RAAS activity and developed oxidative stress are involved in the pathogenesis of hypertension (12,26,55) and are a hallmark in cardiovascular diseases that often develop from prolonged hypertension. In heart failure, we (19) have previously demonstrated that oxidative stress in the muscle plays a role in exaggerating the exercise pressor reflex.…”

“…The activity of the renin-angiotensin-aldosterone system (RAAS) is increased in hypertension (12). ANG II, an effector molecule of the RAAS, plays an important role in developing and maintaining hypertension by constricting vessels via its action on smooth muscle cells (5,14).…”

In vivo key role of reactive oxygen species and NHE-1 activation in determining excessive cardiac hypertrophy

“…This pathway also involves NADPH oxidase (NOX)-dependent mitochondrial reactive oxygen species (ROS) release, which itself activates the p90 RSK -NHE-1 redoxsensitive kinase, among others (for review, see Ref. [22]). Recently, Nakamura et al [40] demonstrated in vitro that NHE-1 hyperactivity is sufficient to generate Ca +2 signals required for CH to take place.…”

Modulation of angiotensin II-induced inflammatory cytokines by the Epac1-Rap1A-NHE3 pathway: implications in renal tubular pathobiology

“…Overall, the information gathered from many clinical literature reports supplemented with in vivo experiments suggests that the biology of the RAS or ANG II, oxidant stress, and inflammatory cytokines is intertwined such that the pathological effects manifest in all the compartments of the kidney, like in chronic kidney disease, such as diabetic nephropathy and tubulointerstitial fibrosis (47,53,75). Interestingly, the oxidant stress whether originating because of inflammation or ANG II stimulation can upregulate ANG II type 1 receptor (AT 1 R) with a multitude of responses, including activation of signaling pathways and transcription factors (6,18). One of the important transcription factors that is induced by ANG II or following AT 1 R or AT 2 R upregulation or activation of small GTPase (Rho-kinase) seems to be NF-B.…”