Apical P2XR contribute to [Ca2+]i signaling and Isc in mouse renal MCD

Li, Liuzhe; Lynch, I. Jeanette; Zheng, Wencui; Cash, Melanie N.; Teng, Xueling; Wingo, Charles S.; Verlander, Jill W.; Xia, Shen‐Ling

doi:10.1016/j.bbrc.2007.05.143

Cited by 11 publications

(12 citation statements)

References 27 publications

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“…6,[27][28][29][30][31][32][33][34][35][36][37][38][39] They also extend the findings of an earlier study in which, using Na ϩ -replete rats and a limited number of commercially available P2R antibodies, we demonstrated a variety of P2R expressed throughout the nephron. 40 …”

Section: P2r Expression In the CDsupporting

confidence: 82%

Sodium-Dependent Regulation of Renal Amiloride-Sensitive Currents by Apical P2 Receptors

Wildman

Marks

Turner

et al. 2008

Journal of the American Society of Nephrology

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The epithelial sodium channel (ENaC) plays a major role in the regulation of sodium balance and BP by controlling Na ϩ reabsorption along the renal distal tubule and collecting duct (CD). ENaC activity is affected by extracellular nucleotides acting on P2 receptors (P2R); however, there remain uncertainties over the P2R subtype(s) involved, the molecular mechanism(s) responsible, and their physiologic role. This study investigated the relationship between apical P2R and ENaC activity by assessing the effects of P2R agonists on amiloride-sensitive current in the rat CD. Using whole-cell patch clamp of principal cells of split-open CD from Na ϩ -restricted rats, in combination with immunohistochemistry and real-time PCR, we found that activation of metabotropic P2R (most likely the P2Y 2 and/or 4 subtype), via phospholipase C, inhibited ENaC activity. In addition, activation of ionotropic P2R (most likely the P2X 4 and/or 4/6 subtype), via phosphatidylinositol-3 kinase, either inhibited or potentiated ENaC activity, depending on the extracellular Na ϩ concentration; therefore, it is proposed that P2X 4 and/or 4/6 receptors might function as apical Na ϩ sensors responsible for local regulation of ENaC activity in the CD and could thereby help to regulate Na ϩ balance and systemic BP.

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Section: P2r Expression In the CDsupporting

confidence: 82%

Sodium-Dependent Regulation of Renal Amiloride-Sensitive Currents by Apical P2 Receptors

Wildman

Marks

Turner

et al. 2008

Journal of the American Society of Nephrology

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“…mRNA for P2Y 1, 2, 4 and 6 subtypes was identified in the inner medullary collecting duct (IMCD) [188,433]. P2X1, 4, 5, 6 and 7 mRNAs have been localised to the murine cortical and outer medullary collecting duct, indicative of species differences in expression profiles [219]. In humans, only P2X4 has been detected in significant amounts in the collecting duct [50].…”

Section: Distal Tubulesmentioning

confidence: 99%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

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The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine-and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.

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“…Activation of luminal P2X receptors (likely P2X 1&4 ) in the collecting duct promotes Ca 2ϩ entry and mobilization in mice and rats (22,23). Activation of apical P2Y receptors (perhaps P2Y 2 ) also promotes Ca 2ϩ signaling, which, in some cases results in activation of Cl Ϫ channels, in mouse and rat collecting duct cells (11,12,14,24).…”

Section: Systemic Namentioning

confidence: 99%

Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

Pochynyuk

Bugaj

Rieg

et al. 2008

Journal of Biological Chemistry

122

166

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Growing evidence implicates a key role for extracellular nucleotides in cellular regulation, including of ion channels and renal function, but the mechanisms for such actions are inadequately defined. We investigated purinergic regulation of the epithelial Na ؉ channel (ENaC) in mammalian collecting duct. We find that ATP decreases ENaC activity in both mouse and rat collecting duct principal cells. ATP and other nucleotides, including UTP, decrease ENaC activity via apical P2Y 2 receptors. ENaC in collecting ducts isolated from mice lacking this receptor have blunted responses to ATP. P2Y 2 couples to ENaC via PLC; direct activation of PLC mimics ATP action. Tonic regulation of ENaC in the collecting duct occurs via locally released ATP; scavenging endogenous ATP and inhibiting P2 receptors, in the absence of other stimuli, rapidly increases ENaC activity. Moreover, ENaC has greater resting activity in collecting ducts from P2Y 2 ؊/؊ mice. Loss of collecting duct P2Y 2 receptors in the knock-out mouse is the primary defect leading to increased ENaC activity based on the ability of direct PLC stimulation to decrease ENaC activity in collecting ducts from P2Y 2 ؊/؊ mice in a manner similar to ATP in collecting ducts from wild-type mice. These findings demonstrate that locally released ATP acts in an autocrine/paracrine manner to tonically regulate ENaC in mammalian collecting duct. Loss of this intrinsic regulation leads to ENaC hyperactivity and contributes to hypertension that occurs in P2Y 2 receptor ؊/؊ mice. P2Y 2 receptor activation by nucleotides thus provides physiologically important regulation of ENaC and electrolyte handling in mammalian kidney. Systemic Naϩ balance influences blood pressure. Consequently, body Na ϩ content is under tight negative-feedback control by the renin-angiotensin-aldosterone system. Discretionary Na ϩ reabsorption in the aldosterone-sensitive distal renal nephron, including the collecting duct, fine-tunes plasma Na ϩ levels. Here, the activity of the luminal epithelial Na ϩ channel (ENaC) 2 is limiting for Na ϩ transport (1-3). ENaC is an end-effector of the renin-angiotensin-aldosterone system with aldosterone increasing ENaC activity. The importance of ENaC and its proper regulation to control of blood pressure is highlighted by several diseases associated with gain and loss of ENaC function (3, 4). For instance, gain of ENaC function results in inappropriate Na ϩ conservation and hypertension (e.g. Liddle syndrome). Conversely, loss of ENaC function results in renal salt wasting associated with hypotension (e.g. pseudohypoaldosteronism type 1).Although extrinsic regulation of ENaC in the distal nephron by hormones originating outside the kidney is considered pivotal to blood pressure control, complementary regulation of ENaC by autocrine/paracrine factors originating from intrarenal sources is just now becoming appreciated. ATP has been identified as a candidate signaling molecule possibly mediating intrinsic control of distal nephron Na ϩ reabsorption (5-14). ATP and other...

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Apical P2XR contribute to [Ca2+]i signaling and Isc in mouse renal MCD

Cited by 11 publications

References 27 publications

Sodium-Dependent Regulation of Renal Amiloride-Sensitive Currents by Apical P2 Receptors

Sodium-Dependent Regulation of Renal Amiloride-Sensitive Currents by Apical P2 Receptors

Purinergic signalling in the kidney in health and disease

Paracrine Regulation of the Epithelial Na+ Channel in the Mammalian Collecting Duct by Purinergic P2Y2 Receptor Tone

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