The Flame That Lights the Fire
Oxidative Stress, Inflammation, and Renal Damage in Angiotensin II–Induced Hypertension
Low-grade inflammation has acquired progressive recognition over the past few years as a mechanism for cardiovascular and renal damage. In hypertension, the activation of inflammatory mediators has been demonstrated in blood vessels, the heart, and the kidney in angiotensin (Ang) II–dependent models of hypertension, such as human angiotensinogen/human renin double transgenic rats1 and rats infused with Ang II,2 or in mineralocorticoid-induced hypertension.3
Both Ang II and endothelin-1 trigger an inflammatory process that participates in the mechanisms of hypertension. In a mouse model deficient in macrophages, the osteopetrotic mouse, Ang II- and endothelin-1–dependent hypertension were blunted together with oxidative stress generation, inflammatory mediator expression, vascular remodeling, and endothelial dysfunction.4,5 In human hypertension, inflammatory biomarkers, specifically C-reactive protein but also others, predict incident hypertension.6
Ang II exerts proinflammatory effects by stimulating redox-sensitive signaling cascades leading to mitogen-activated protein kinase activation, more specifically, p38 mitogen-activated protein kinase. Oxidative stress then stimulates inflammatory mediators, including nuclear factor κB and activator protein-1. These, in turn, trigger production of chemokines, such as monocyte chemoattractant peptide-1, involved in macrophage recruitment, and activation of proinflammatory and prothrombotic agents, such as plasminogen activator inhibitor-1, and adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1.7 These inflammatory actions may require the participation of T-lymphocytes, important mediators in Ang II–induced hypertension. Guzik et al8 have shown that mice lacking T and B cells (RAG-1−/− mice) have blunted hypertension and do not develop abnormalities of vascular function during Ang II infusion or exposure to deoxycorticosterone acetate-salt, changes that are restored by transfer of T but not B cells. Transfer of T cells lacking the Ang II type 1 receptor or a functional reduced nicotinamide-adenine dinucleotide phosphate oxidase resulted in blunted Ang II–dependent hypertension and decreased vascular superoxide generation. Ang II increases T-cell markers of activation and stimulates infiltration of T cells in periadventitial fat and adventitia of aorta accompanied by increased intercellular adhesion molecule-1 and RANTES.8
In this issue, Liao et al9 use a mouse model of gene inactivation of chemokine receptor (CCR)2, of which the natural ligand is monocyte chemoattractant peptide-1, and demonstrate that Ang II infusion does not induce the same degree of inflammation and renal dysfunction in the CCR2−/− mice as in wild-type mice. Oxidative stress, macrophage infiltration, albuminuria, and renal damage were significantly lower and glomerular filtration rate higher in CCR2−/− mice than in CCR2+/+ mice infused with Ang II. These data are in agreement with previous results on the role of inflammation in kidney damage in human renin/human angiotensinogen double transgenic rats1 and the blunted vascular inflammation and damage found in previous studies of CCR2−/− mice infused with Ang II.10
Although, in the study of Liao et al,9 reduced inflammation in the kidney was associated with blunted oxidative stress generation, blood pressure (BP) increased in CCR2−/− mice similarly to the wild-type mice, which led the authors to conclude that oxidative stress, while mediating inflammation in the kidney leading to renal dysfunction, does not influence BP. This agrees with previous data from other investigators who showed that reactive oxygen species in mice were not involved in either cardiac hypertrophy or BP elevation in Ang II–infused mice but could play a role in the kidney. Touyz et al11 crossed gp91phox-deficient mice with transgenic mice expressing active human renin in the liver (TTRhRen), which develop chronic Ang II–dependent hypertension and cardiac hypertrophy. Although reactive oxygen species were significantly reduced in the heart and aorta of TTRhRen/gp91− mice, and this was associated with reduced cardiac, aortic, and renal reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity, gp91phox inactivation had no effect on the development of hypertension or cardiac hypertrophy in TTRhRen mice. Recently, Yogi et al12 demonstrated that, in the Nox1-deficient TTRhRen mice, BP was elevated despite attenuated NADPH oxidase activation and decreased reactive oxygen species and redox signaling. Thus, the work of Liao et al9 extends to inflammation these studies that showed that Nox1-containing NADPH oxidase plays a key role in the modulation of systemic and renal oxidative stress but not in the elevation of BP in chronic Ang II–dependent hypertension. However, these data are not in agreement with BP effects of reactive oxygen species in rats infused with Ang II.13
These discrepancies may relate to biological differences between the strains of mice used by Liao et al9 and the animal models reported in the other publications or experimental differences between studies and, thus, require caution in interpretation of all of these data. They may indicate that dependency of BP regulation on oxidative stress occurs only in some animal models. Findings from the present study should not be interpreted to mean that there is no role for oxidative stress in BP elevation in humans. A caveat that cannot be forgotten, however, is that most human trials of antioxidants in hypertension have failed to either lower BP or result in improved cardiovascular outcomes, whereas some rat models of hypertension have responded favorably.14 This again may relate to populations studied, design of trials, or mechanism of action and bioavailability of antioxidants used. Thus, the relationship of BP to oxidative stress and that of hypertrophy to oxidative stress in the heart11 remains unclear. However, oxidative stress and inflammation seem clearly linked in the kidney, as demonstrated by Liao et al.9 The present study, thus, raises some questions, such as the exact involvement of oxidative stress in cardiovascular damage and BP elevation, whereas at the same time it extends our appreciation of the mechanistic role of oxidative stress-triggered inflammation in renal dysfunction resulting from the actions of Ang II.
Sources of Funding
Work by E.L.S. was funded by grants 37917 and 82790 from the Canadian Institutes of Health Research, by the Canada Research Chairs Program of the Government of Canada, and by a Canada Research Chairs infrastructure grant from the Canadian Fund for Innovation.
E.L.S. has received research grants (more than $10 000) from Merck-Frosst and Pfizer in the last year and has participated in advisory boards and been part of the speakers bureau of Boehringer-Ingelheim and Novartis (less than $10 000).
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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