Autoantibody-Mediated Angiotensin Receptor Activation Contributes to Preeclampsia Through Tumor Necrosis Factor-α Signaling

Irani, Roxanna A.; Zhang, Yujin; Zhou, Cissy Chenyi; Hicks, M. John; Ramin, Susan M.; Kellems, Rodney E.; Xia, Yang

doi:10.1161/hypertensionaha.110.150540

Cited by 80 publications

(77 citation statements)

References 53 publications

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“…24 TNFα blockade has also proven effective in either reducing blood pressure or protecting against renal injury in various models of hypertension including pre-eclampsia, a model of lupus erythematosus, angiotensin II infusion in rats, transgenic rats and fructose feeding. 27, 64–67 Despite the fact that TNFα antagonists have been used extensively to treat humans with a variety of autoimmune diseases, there is no evidence that they have blood pressure lowering effects. There are conflicting reports that these agents affect vascular stiffness in humans.…”

Section: Cytokines Contributing To Hypertensionmentioning

confidence: 99%

Inflammation, Immunity, and Hypertensive End-Organ Damage

McMaster

Kirabo

Madhur

et al. 2015

Circulation Research

559

425

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For more than 50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, DOCA-salt and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including IL-17, IFN-γ, TNFα and IL-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption and increased renal fibrosis. Very recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension including myocardial infarction, heart failure, renal failure and stroke.

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Section: Cytokines Contributing To Hypertensionmentioning

confidence: 99%

Inflammation, Immunity, and Hypertensive End-Organ Damage

McMaster

Kirabo

Madhur

et al. 2015

Circulation Research

559

425

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“…The fibrotic areas stained in light blue were picked up on the digital images using a computerized densitometry (ImagePro Plus, version 6.0; Media Cybernetics, Silver Spring, MD) coupled to a microscope equipped with a digital camera as described. 50,51 The percentage of the fibrotic area relative to the whole area of the field was calculated (percent fibrosis area). The average densities of 10 areas per kidney were averaged, the SEM is indicated, and n ϭ 4 to 6 kidneys for each category.…”

Section: Morphometric Analysis Of the Renal Fibrosis In Masson's Tricmentioning

confidence: 99%

A2B Adenosine Receptor–Mediated Induction of IL-6 Promotes CKD

Dai¹,

Zhang²,

Wen³

et al. 2011

Journal of the American Society of Nephrology

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Chronic elevation of adenosine, which occurs in the setting of repeated or prolonged tissue injury, can exacerbate cellular dysfunction, suggesting that it may contribute to the pathogenesis of CKD. Here, mice with chronically elevated levels of adenosine, resulting from a deficiency in adenosine deaminase (ADA), developed renal dysfunction and fibrosis. Both the administration of polyethylene glycol-modified ADA to reduce adenosine levels and the inhibition of the A 2B adenosine receptor (A 2B R) attenuated renal fibrosis and dysfunction. Furthermore, activation of A 2B R promoted renal fibrosis in both mice infused with angiotensin II (Ang II) and mice subjected to unilateral ureteral obstruction (UUO). These three mouse models shared a similar profile of profibrotic gene expression in kidney tissue, suggesting that they share similar signaling pathways that lead to renal fibrosis. Finally, both genetic and pharmacologic approaches showed that the inflammatory cytokine IL-6 mediates adenosine-induced renal fibrosis downstream of A 2B R. Taken together, these data suggest that A 2B R-mediated induction of IL-6 contributes to renal fibrogenesis and shows potential therapeutic targets for CKD.

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“…In addition, healthy endothelial cells incubated with serum from preeclamptic rats exhibited increased endothelin-1 release and this was prevented by etanercept (79). Similarly, infusion of a neutralizing anti-TNF antibody reduced blood pressure, albuminuria, and renal damage in a model of preeclampsia achieved by adoptive transfer of serum from preeclamptic women to pregnant mice (62).…”

mentioning

confidence: 96%