Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity

Barr, Travis P.; Hrnjic, Alen; Khodorova, Alla; Sprague, Jared; Strichartz, Gary R.

doi:10.1016/j.pain.2014.02.014

Cited by 17 publications

(15 citation statements)

References 34 publications

(50 reference statements)

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“…Despite their overlapping spheres of influence, information on potential interplay between renal P2 and ET receptors is rare. The interaction between ET-1 and P2 signaling systems has been also demonstrated in extrarenal tissues (1,4,31,35). Our current findings demonstrate that activation of medullary P2 receptors promotes ET-1-dependent natriuresis in OVX rats, similar to male rats (23).…”

Section: Discussionsupporting

confidence: 75%

Ovariectomy uncovers purinergic receptor activation of endothelin-dependent natriuresis

Gohar

Kasztan

Becker

et al. 2017

American Journal of Physiology-Renal Physiology

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We recently reported that natriuresis produced by renal medullary salt loading is dependent on endothelin (ET)-1 and purinergic (P2) receptors in male rats. Because sex differences in ET-1 and P2 signaling have been reported, we decided to test whether ovarian sex hormones regulate renal medullary ET-1 and P2-dependent natriuresis. The effect of medullary NaCl loading on Na excretion was determined in intact and ovariectomized (OVX) female Sprague-Dawley rats with and without ET-1 or P2 receptor antagonism. Isosmotic saline (284 mosmol/kgHO) was infused in the renal medullary interstitium of anesthetized rats during a baseline urine collection period, followed by isosmotic or hyperosmotic saline (1,800 mosmol/kgHO) infusion. Medullary NaCl loading significantly enhanced Na excretion in intact and OVX female rats. ET or P2 receptor blockade did not attenuate the natriuretic effect of medullary NaCl loading in intact females, whereas ET or P2 receptor blockade attenuated the natriuretic response to NaCl loading in OVX rats. Activation of medullary P2Y and P2Y receptors by UTP infusion had no significant effect in intact females but enhanced Na excretion in OVX rats. Combined ET receptor blockade significantly inhibited the natriuretic response to UTP observed in OVX rats. These data demonstrate that medullary NaCl loading induces ET-1 and P2-independent natriuresis in intact females. In OVX, activation of medullary P2 receptors promotes ET-dependent natriuresis, suggesting that ovarian hormones may regulate the interplay between the renal ET-1 and P2 signaling systems to facilitate Na excretion.

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Section: Discussionsupporting

confidence: 75%

Ovariectomy uncovers purinergic receptor activation of endothelin-dependent natriuresis

Gohar

Kasztan

Becker

et al. 2017

American Journal of Physiology-Renal Physiology

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“…P2X4 receptors and related purinergic mechanisms involved in T cell migration may be promising therapeutic targets in lung transplantation, as suggested by previous work showing that P2X receptor antagonists could dramatically improve long-term graft survival in a mouse lung transplant model (52). Future studies will be needed to evaluate the pharmacokinetics of 5-BDBD, to refine currently used drug regimens (53,54), and to study the efficacy of this and future P2X4 receptor antagonists in the prevention of chronic lung allograft rejection.…”

Section: Discussionmentioning

confidence: 99%

Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration

Ledderose¹,

Liu²,

Kondo³

et al. 2018

Journal of Clinical Investigation

116

148

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T cells must migrate in order to encounter antigen-presenting cells (APCs) and to execute their varied functions in immune defense and inflammation. ATP release and autocrine signaling through purinergic receptors contribute to T cell activation at the immune synapse that T cells form with APCs. Here, we show that T cells also require ATP release and purinergic signaling for their migration to APCs. We found that the chemokine stromal-derived factor-1α (SDF-1α) triggered mitochondrial ATP production, rapid bursts of ATP release, and increased migration of primary human CD4+ T cells. This process depended on pannexin-1 ATP release channels and autocrine stimulation of P2X4 receptors. SDF-1α stimulation caused localized accumulation of mitochondria with P2X4 receptors near the front of cells, resulting in a feed-forward signaling mechanism that promotes cellular Ca2+ influx and sustains mitochondrial ATP synthesis at levels needed for pseudopod protrusion, T cell polarization, and cell migration. Inhibition of P2X4 receptors blocked the activation and migration of T cells in vitro. In a mouse lung transplant model, P2X4 receptor antagonist treatment prevented the recruitment of T cells into allograft tissue and the rejection of lung transplants. Our findings suggest that P2X4 receptors are therapeutic targets for immunomodulation in transplantation and inflammatory diseases.

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“…Furthermore, nonrenal studies demonstrated that purinergic and ET-1 signaling interact in sensory neurons (5), blood vessels (1, 13), as well as myocardium (10). Barr et al (5) provided evidence that mechanical hypersensitivity caused by cutaneous ET-1 involves sensitization of P2X 4 receptors. In porcine pancreatic arteries, P2Y 14 receptor plays vasocontractile role that involves the release of ET-1 (1).…”

Section: Discussionmentioning

confidence: 99%

Activation of purinergic receptors (P2) in the renal medulla promotes endothelin-dependent natriuresis in male rats

Gohar

Speed

Kasztan

et al. 2016

American Journal of Physiology-Renal Physiology

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vation of purinergic receptors (P2) in the renal medulla promotes endothelin-dependent natriuresis in male rats. Am J Physiol Renal Physiol 311: F260 -F267, 2016. First published May 25, 2016 doi:10.1152/ajprenal.00090.2016.-Renal endothelin-1 (ET-1) and purinergic signaling systems regulate Na ϩ reabsorption in the renal medulla. A link between the renal ET-1 and purinergic systems was demonstrated in vitro, however, the in vivo interaction between these systems has not been defined. To test whether renal medullary activation of purinergic (P2) receptors promotes ET-dependent natriuresis, we determined the effect of increased medullary NaCl loading on Na ϩ excretion and inner medullary ET-1 mRNA expression in anesthetized adult male Sprague-Dawley rats in the presence and absence of purinergic receptor antagonism. Isosmotic saline (NaCl; 284 mosmol/kgH2O) was infused into the medullary interstitium (500 l/h) during a 30-min baseline urine collection period, followed by isosmotic or hyperosmotic saline (1,800 mosmol/kgH2O) for two further 30-min urine collection periods. Na ϩ excretion was significantly increased during intramedullary infusion of hyperosmotic saline. Compared with isosmotic saline, hyperosmotic saline infused into the renal medulla caused significant increases in inner medullary ET-1 mRNA expression. Renal intramedullary infusion of the P2 receptor antagonist suramin inhibited the increase in Na ϩ excretion and inner medullary ET-1 mRNA expression induced by NaCl loading in the renal medulla. Activation of medullary P2Y2/4 receptors by infusion of UTP increased urinary Na ϩ excretion. Combined ETA and ETB receptor blockade abolished the natriuretic response to intramedullary infusion of UTP. These data demonstrate that activation of medullary P2 receptors promotes ET-dependent natriuresis in male rats, suggesting that the renal ET-1 and purinergic signaling systems interact to efficiently facilitate excretion of a NaCl load.endothelin-1; purinergic receptors; natriuresis; kidney; inner medulla ENDOTHELIN-1 (ET-1) is an autocrine inhibitor of Na ϩ and water reabsorption by the kidney and plays a central role for the regulation of Na ϩ homeostasis and blood pressure control. Within the renal medulla, ET-1 is released in response to a high-salt diet and inhibits tubular Na ϩ transport promoting natriuresis (14, 17). It appears that both ET A and ET B receptors are required for the full diuretic and natriuretic effects of ET-1 (7). However, the signaling mechanism by which NaCl loading to the renal medulla translates into an increase in ET-1 production and/or action is currently unknown.Purinergic signaling has also emerged as another important system in the renal control of blood pressure and Na ϩ excretion (19,31). In response to increased tubular flow, ATP is released from renal tubular cells inhibiting Na ϩ transport along the nephron (12, 19), mainly through P2Y 2 receptor activation (18, 23). Both P2Y 2 knockout mice and ET B -deficient rats develop salt-sensitive hypertension (23, 30), suppo...

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Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity

Cited by 17 publications

References 34 publications

Ovariectomy uncovers purinergic receptor activation of endothelin-dependent natriuresis

Ovariectomy uncovers purinergic receptor activation of endothelin-dependent natriuresis

Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration

Activation of purinergic receptors (P2) in the renal medulla promotes endothelin-dependent natriuresis in male rats

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