γδT Cell–Derived Interleukin-17A via an Interleukin-1β–Dependent Mechanism Mediates Cardiac Injury and Fibrosis in Hypertension

Li, Yulin; Wu, Yina; Zhang, Congcong; Li, Ping; Cui, Wei; Hao, Jianlei; Ma, Xin‐Liang; Yin, Zhinan; Du, Jie

doi:10.1161/hypertensionaha.113.02604

Cited by 70 publications

(67 citation statements)

References 33 publications

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“…It is conceivable that at least a part of the diuretic/natriuretic mechanism of 8-aminoguanosine and 8-aminoguanine involves inhibition of PNPase. Importantly, inhibition of PNPase suppresses T cell function (Bennett et al, 1993), and inflammation mediated by T cells is now clearly understood to importantly contribute to both the etiology of hypertension and hypertension-induced target organ damage (Guzik and Mikolajczyk, 2014;Ji et al, 2014;Li et al, 2014;Pollow et al, 2014). Therefore, we hypothesize that, because 8-aminoguanosine and 8-aminoguanine inhibit PNPase, these compounds may be effective antihypertensive agents that not only reduce blood pressure but also attenuate target organ damage.…”

Section: Pharmacology Of 8-substituted Guanosines and Guaninesmentioning

confidence: 91%

8-Aminoguanosine and 8-Aminoguanine Exert Diuretic, Natriuretic, Glucosuric, and Antihypertensive Activity

Jackson

Gillespie

2016

J Pharmacol Exp Ther

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In vivo, guanine moieties in DNA, RNA, guanine nucleotides, or guanosine or guanine per se can undergo nitration (for example, by peroxynitrite) or hydroxylation (for example, by superoxide anion) on position 8 of the purine ring. Subsequent catabolism of these modified biomolecules leads to the production of a diverse group of 8-nitro, 8-amino, and 8-hydroxy guanosine and guanine compounds. Indeed, studies suggest the in vivo existence of 8-nitroguanosine, 8-nitroguanine, 8-aminoguanosine, 8-aminoguanine, 8-hydroxyguanosine, 8-hydroxy-29-deoxyguanosine, and 8-hydroxyguanine. Since a multitude of these compounds exist in vivo, and since the renal effects of 8-substituted guanosine and guanine compounds are entirely unknown, we examined the effects of guanosine, guanine, 8-nitroguanosine, 8-nitroguanine, 8-hydroxyguanosine, 8-hydroxyguanine, 8-hydroxy-29-deoxyguanosine, 8-aminoguanosine, and 8-aminoguanine (33.5 mmol/kg/min; intravenous infusion for 115 minutes) on excretion of sodium, potassium, and glucose in rats. Guanosine, 8-nitroguanosine, and 8-hydroxy-29-deoxyguanosine had minimal natriuretic activity. Guanine, 8-nitroguanine, 8-hydroxyguanosine, and 8-hydroxyguanine had moderate natriuretic activity (increased sodium excretion by 9.4-, 7.8-, 7.1-, and 8.6-fold, respectively). In comparison with all other compounds, 8-aminoguanosine and 8-aminoguanine were highly efficacious and increased sodium excretion by 26.6-and 17.2-fold, respectively, exceeding that of a matched dose of amiloride (13.6-fold increase). 8-Aminoguanosine and 8-aminoguanine also increased glucose excretion by 12.1-and 12.2-fold, respectively, and decreased potassium excretion by 69.1 and 71.0%, respectively. Long-term radiotelemetry studies demonstrated that oral 8-aminoguanosine and 8-aminoguanine (5 mg/kg/day) suppressed deoxycorticosterone/salt-induced hypertension. These experiments demonstrate that some naturally occurring 8-substitued guanosine and guanine compounds, particularly 8-aminoguanosine and 8-aminoguanine, are potent and efficacious potassium-sparing diuretics/natriuretics that may represent a novel class of antihypertensive diuretics.

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Section: Pharmacology Of 8-substituted Guanosines and Guaninesmentioning

confidence: 91%

8-Aminoguanosine and 8-Aminoguanine Exert Diuretic, Natriuretic, Glucosuric, and Antihypertensive Activity

Jackson

Gillespie

2016

J Pharmacol Exp Ther

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“…Ang II infusion increases IL-17A production by T cells and IL-17 protein in the aortic media and the heart. 47 The initial hypertensive response to Ang II infusion is similar in IL-17A 2/2 mice and wild-type mice. However, hypertension is not sustained in IL-17A 2/2 mice, T-bet-and IFN-g deficiency have no effect on BP but less vascular dysfunction in response to Ang II infusion 37 Effect of neutralizing antibodies IFN-g antibody has no effect on BP in hypertensive NZB mice reaching levels 30 mmHg lower than in wild-type mice by 4 weeks of Ang II infusion.…”

Section: T H 1 and T Hmentioning

confidence: 92%

“…48 In addition, mice lacking IL-17A are also protected against aortic stiffening and cardiac fibrosis after infusion of Ang II. 47,49 Obviously, gd T cell-derived IL-17 mediates the adverse effects of IL-17 in hypertension. 47 In addition, IL-17 treatment increased systolic BP in mice.…”

Section: T H 1 and T Hmentioning

confidence: 99%

See 1 more Smart Citation

Immune Mechanisms in Arterial Hypertension

Wenzel¹,

Turner²,

Krebs³

et al. 2016

Journal of the American Society of Nephrology

171

148

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Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to hemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign organisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Renal inflammation results in injury and impaired urinary sodium excretion, and vascular inflammation leads to endothelial dysfunction, increased vascular resistance, and arterial remodeling and stiffening. Notably, modulation of the immune response can reduce the severity of BP elevation and hypertensive endorgan damage in several animal models. Indeed, recent studies have improved our understanding of how the immune response affects the pathogenesis of arterial hypertension, but the remarkable advances in basic immunology made during the last few years still await translation to the field of hypertension. This review briefly summarizes recent advances in immunity and hypertension as well as hypertensive end-organ damage.

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“…4 Interestingly, subsequent studies showed that the genetic removal of monocytes also protected mice from severe hypertension, in part, through the natural killer cell-dependent mechanisms. 7,8 This demonstrates the complexity of the immune activation in hypertension, which is addressed by Li et al 9 in the current issue of Hypertension. Understanding of these novel, immune mechanisms of hypertension will create the possibility of immunomodulatory approaches in the treatment hypertension.…”

mentioning

confidence: 75%