Extracellular nucleotide signaling along the renal epithelium

Schwiebert, Erik M.; Kishore, Bellamkonda

doi:10.1152/ajprenal.2001.280.6.f945

Cited by 148 publications

(186 citation statements)

References 139 publications

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“…Here, maximal inhibition (56% by apical UTP and 44% by basolateral UTP) occurred within 10 min. The IC 50 value for UTP inhibition was 500 nM, a concentration that matches the extracellular levels of ATP estimated in tubular fluid [18]. Of note, the proposed P2R subtype responsible for this inhibition was equally sensitive to UTP and ATP.…”

Section: Enac Modulation By P2rs In the Kidneysupporting

confidence: 60%

“…ATP, and other signalling nucleotides, are now known to be released from epithelial cells in measured amounts, and in a polarised manner, in response to such diverse stimuli as mechanical stimulation (e.g. stretch and osmotic swelling), local acidosis and hypoxia [18][19][20][21] (and see article by Praetorius and Leipziger [22] in this Special Issue). The process of ATP release involves a number of complementary pathways that include transport via ATPbinding-cassette (ABC) proteins [23], connexin hemichannels [24], large-diameter anion channels [25] and exocytotic vesicular release [26].…”

Section: Atp and Its Surface Receptorsmentioning

confidence: 99%

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ENaC, renal sodium excretion and extracellular ATP

Wildman

Kang

King

2009

Purinergic Signalling

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Sodium balance determines the extracellular fluid volume and sets arterial blood pressure (BP). Chronically raised BP (hypertension) represents a major health risk in Western societies. The relationship between BP and renal sodium excretion (the pressure/natriuresis relationship) represents the key element in defining the BP homeostatic set point. The renin-angiotensin-aldosterone system (RAAS) makes major adjustments to the rates of renal sodium secretion, but this system works slowly over a period of hours to days. More rapid adjustments can be made by the sympathetic nervous system, although the kidney can function well without sympathetic nerves. Attention has now focussed on regulatory mechanisms within the kidney, including extracellular nucleotides and the P2 receptor system. Here, we discuss how extracellular ATP can control renal sodium excretion by altering the activity of epithelial sodium channels (ENaC) present in the apical membrane of principal cells. There remains considerable controversy over the molecular targets for released ATP, although the P2Y 2 receptor has received much attention. We review the available data and reflect on our own findings in which ATP-activated P2Y and P2X receptors make adjustments to ENaC activity and therefore sodium excretion.

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Section: Enac Modulation By P2rs In the Kidneysupporting

confidence: 60%

Section: Atp and Its Surface Receptorsmentioning

confidence: 99%

ENaC, renal sodium excretion and extracellular ATP

Wildman

Kang

King

2009

Purinergic Signalling

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“…In renal epithelial cells, ATP is released from the cell in a polarized manner, either at the apical or basolateral cell surfaces, for the purpose of autocrine and paracrine regulation of the epithelial function (21,22). It is important to recognize the very different effects of ATP when released into the basolateral as compared with the apical compartment.…”

Section: Resultsmentioning

confidence: 99%

Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Gorelik

Zhang

Sánchez

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Aldosterone, the most important sodium-retaining hormone, was first characterized >50 years ago. However, despite numerous studies including the classical work of Isidore S. ''Izzy'' Edelman showing that aldosterone action depended on ATP production, the mechanism by which it activates sodium reabsorption via the epithelial sodium channel remains unclear. Here, we report experiments that suggest that one of the key steps in aldosterone action is via an autocrine͞paracrine system. The hormone stimulates ATP release from the basolateral side of the target kidney cell. Prevention of ATP accumulation or its removal blocks aldosterone action. ATP then acts via a purinergic mechanism to produce contraction of small groups of adjacent epithelial cells. Patch clamping demonstrates that it is these contracted cells that have channel activity. With progressive recruitment of contracting cells, there is then a parallel increase in transepithelial electrical conductance. In common with other stimuli of sodium transport, this pathway involves phosphatidylinositol 3-kinase. Inhibition of phosphatidylinositol 3-kinase blocks both cell contraction and conductance. We put forward the hypothesis that redistribution of the cell volume caused by the lateral contraction results in apical swelling and that this change, in turn, disrupts the epithelial sodium channel interaction with the F-actin cytoskeleton, opening the channel and hence increasing sodium transport.scanning ion conductance microscopy ͉ scanning probe microscopy ͉ epithelial sodium channel ͉ renal epithelium T he sodium homeostasis regulatory hormone aldosterone was first identified in 1953 (1). Early studies on the biochemical mechanism of its action were reviewed by Edelman and Fimognari (2). This work was greatly helped by the introduction by Ussing and Zerahn (3) of the short-circuit current method for measuring sodium transport. Jean Crabbé (4, 5) first demonstrated the effect of aldosterone on sodium transport across toad bladder and skin and drew attention to the latent period of 60-90 min in the action of aldosterone. He postulated the synthesis or activation of an intermediate by aldosterone. Work by Edelman et al. (6) showed that inhibition of DNA-dependent RNA synthesis and of protein synthesis blocked the aldosterone effect. Edelman et al. (6) went on to demonstrate that aldosterone activation of sodium transport was critically dependent on ATP production. In substrate-depleted toad bladders, aldosterone had little or no effect, but the response was restored by adding glucose or pyruvate to the medium. Edelman suggested that a possible explanation of this absolute dependence on substrate was that, in the energy-depleted system, the rate of activation of sodium transport was limited by the local concentration of ATP. However, he felt that this hypothesis was questionable given that substrate-depleted toad bladders responded to vasopressin and to amphotericin B with a normal increase in sodium transport. This work became known as the ATP generation hypothe...

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“…Adenosine 5′-triphosphate (ATP) can be released from renal epithelial cells across the apical membrane into the tubular lumen and also, to a lesser extent, across the basolateral membrane [1,2]. As described elsewhere in this Special Issue, these nucleotides have the potential to activate renal P2 purinoceptors located along the nephron and thereby elicit a variety of autocrine/paracrine effects on tubular transport processes.…”

Section: Introductionmentioning

confidence: 99%

Ectonucleotidases in the kidney

Shirley

Vekaria

Sévigny

2009

Purinergic Signalling

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Members of all four families of ectonucleotidases, namely ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase/ phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatases, have been identified in the renal vasculature and/or tubular structures. In rats and mice, NTPDase1, which hydrolyses ATP through to AMP, is prominent throughout most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct. NTPDase2 and NTPDase3, which both prefer ATP over ADP as a substrate, are found in most nephron segments beyond the proximal tubule. NPPs catalyse not only the hydrolysis of ATP and ADP, but also of diadenosine polyphosphates. NPP1 has been identified in proximal and distal tubules of the mouse, while NPP3 is expressed in the rat glomerulus and pars recta, but not in more distal segments. Ecto-5′-nucleotidase, which catalyses the conversion of AMP to adenosine, is found in apical membranes of rat proximal convoluted tubule and intercalated cells of the distal nephron, as well as in the peritubular space. Finally, an alkaline phosphatase, which can theoretically catalyse the entire hydrolysis chain from nucleoside triphosphate to nucleoside, has been identified in apical membranes of rat proximal tubules; however, this enzyme exhibits relatively high K m values for adenine nucleotides. Although information on renal ectonucleotidases is still incomplete, the enzymes' varied distribution in the vasculature and along the nephron suggests that they can profoundly influence purinoceptor activity through the hydrolysis, and generation, of agonists of the various purinoceptor subtypes. This review provides an update on renal ectonucleotidases and speculates on the functional significance of these enzymes in terms of glomerular and tubular physiology and pathophysiology.

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Extracellular nucleotide signaling along the renal epithelium

Cited by 148 publications

References 139 publications

ENaC, renal sodium excretion and extracellular ATP

ENaC, renal sodium excretion and extracellular ATP

Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Ectonucleotidases in the kidney

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