Vasoconstrictor and Vasodilator Effects of Adenosine in the Mouse Kidney due to Preferential Activation of A1 or A2 Adenosine Receptors

Hansen, Pernille; Hashimoto, Seiji; Oppermann, Mona; Huang, Yuning; Briggs, Josie P.; Schnermann, Jürgen

doi:10.1124/jpet.105.091017

Cited by 69 publications

(63 citation statements)

References 35 publications

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“…In contrast, selective augmentation of adenosine around afferent arterioles causes persistent vasoconstriction, involving Adora1a. Thus, adenosine is a renal constrictor only when it can interact with afferent arteriolar Adora1a without affecting the bulk of renal Adora2a at the same time (61). Other studies have shown that ENT inhibition with dipyridamole is associated with an initial constriction of the afferent and efferent arterioles at an early phase and subsequent dilation at a later phase, with the same degree of vasoconstrictive and vasodilatory effect on both arterioles in rats (62).…”

Section: Discussionmentioning

confidence: 97%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2012

J. Clin. Invest.

114

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A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) -a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1 -/-mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications. IntroductionAcute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to days. AKI is frequently caused by an obstruction of renal blood flow (renal ischemia) and represents an important cause of morbidity and mortality of patients (1-3). Indeed, a recent study revealed that only a mild increase (0.3 mg/dl) in the serum creatinine level is associated with a 70% greater risk of death than in patients without this increase (2, 3). Particularly for surgical patients, AKI represents a significant threat. For example, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a rate of AKI of up to 30% (4). Similarly, AKI after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality (5). In addition, patients with sepsis frequently go on to develop AKI, and the combination of moder-

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Section: Discussionmentioning

confidence: 97%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2012

J. Clin. Invest.

114

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“…With regard to adenosineinduced renal vasodilation, a study using an isolatedperfused hydronephrotic rat kidney preparation showed that adenosine-induced dilation of afferent arterioles was mediated by adenosine A 2a receptor-dependent activation of K ATP channels (327). A recent study in mice using intravenous infusion of adenosine indicated that the resulting renal vasodilation is due to adenosine A 2a receptor-mediated activation of endothelial NO synthase (109). Whether the same pathway contributes to medullary vasodilation in response to endogenous adenosine, which probably derives from the abluminal site, remains to be determined.…”

Section: Mechanisms Of Adenosine-mediated Vasoconstriction and Vasmentioning

confidence: 99%

Adenosine and Kidney Function

Vallon

Mühlbauer²,

Oßwald³

2006

Physiological Reviews

396

379

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In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.

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“…##P Ͻ 0.01 vs. single treatment at renal perfusion pressure of 100 mmHg. receptors play important modulatory roles in regulating renal afferent arteriolar tone, and activation of A 2 receptors offsets the counteracting influence of A 1 receptors resulting in vasodilation (10,18,27,35,36,38,41). However, previous studies regarding the function of the A 2 receptors have been focused primarily on A 2A subtype, with the effects of A 2B receptors given less attention.…”

Section: Discussionmentioning

confidence: 93%

“…As the concentration of adenosine increases, the vasodilatory stimulus become predominant (10,18,27,35,36,38,41). Activation of adenosine A 1 receptors in the renal vasculature results in vasoconstriction that reduces the glomerular filtration rate (30, 32) and renal blood flow (4), enhances tubuloglomerular feedback responses (37), and inhibits renin secretion (38).…”

mentioning

confidence: 99%

Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A_2B receptor activation

Feng

Navar

2010

American Journal of Physiology-Renal Physiology

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Feng MG, Navar LG. Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation. Am J Physiol Renal Physiol 299: F310 -F315, 2010. First published May 12, 2010 doi:10.1152/ajprenal.00149.2010.-Adenosine is an important paracrine agent regulating renal vascular tone via adenosine A1 and A2 receptors. While A2B receptor message and protein have been localized to preglomerular vessels, functional evidence on the role of A2B receptors in mediating the vasodilator action of adenosine on afferent arterioles is not available. The present study determined the role of A2B receptors in mediating the afferent arteriolar dilation and compared the effects of A2B and A2A receptor blockade on afferent arterioles. We used the rat in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Single afferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing adenosine or adenosine A2 receptor agonist (CV-1808) along with adenosine A2B and A2A receptor blockers. Adenosine (10 mol/l) caused modest constriction and subsequent superfusion with SCH-58261 (SCH), an A2A receptor blocker, at concentrations up 10 mol/l elicited only slight additional decreases in afferent arteriolar diameter with maximum effect at a concentration of 1 mol/l (Ϫ11.0 Ϯ 2.5%, n ϭ 6, P Ͻ 0.05). However, superfusion of adenosine-treated vessels with MRS-1754 (MRS), an A2B receptor blocker, elicited greater decreases in afferent arteriolar diameter (Ϫ26.0 Ϯ 4.7%, n ϭ 5, P Ͻ 0.01). SCH did not significantly augment the adenosine-mediated afferent constriction elicited by MRS; however, adding MRS after SCH caused further significant vasoconstriction. Superfusion with CV-1808 dilated afferent arterioles (17.2 Ϯ 2.4%, n ϭ 6, P Ͻ 0.01). This effect was markedly attenuated by MRS (Ϫ22.6 Ϯ 2.0%, n ϭ 5, P Ͻ 0.01) but only slightly reduced by SCH (Ϫ9.0 Ϯ 1.1%, n ϭ 5, P Ͻ 0.05) and completely prevented by adding MRS after SCH (Ϫ24.7 Ϯ 1.8%, n ϭ 5, P Ͻ 0.01). These results indicate that, while both A2A and A2B receptors are functionally expressed in juxtamedullary afferent arterioles, the powerful vasodilating action of adenosine predominantly involves A2B receptor activation, which counteracts A1 receptor-mediated vasoconstriction. adenosine receptor antagonists; renal microcirculation; vascular biology; afferent arterioles; kidney ADENOSINE IS AN ENDOGENOUS purine nucleoside derived from the degradation of ATP/AMP and serves as a paracrine agent influencing many physiological processes. Four subtypes of adenosine receptors have been identified: A 1 , A 2A , A 2B , and A 3 ; all are guanine nucleotide-binding protein (G)-coupled receptors (6,15,25,26,28,29), which are characterized by their capacity to either increase or decrease intracellular cAMP levels (13). A 2A and A 2B receptors are coupled to G s protein signaling and mediate biological effects opposite to A 1 and A 3 receptors, which are coupled to G i protein signaling (13). All four subtypes of aden...

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Vasoconstrictor and Vasodilator Effects of Adenosine in the Mouse Kidney due to Preferential Activation of A1 or A2 Adenosine Receptors

Cited by 69 publications

References 35 publications

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Adenosine and Kidney Function

Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A_2B receptor activation

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