Extracellular Nucleotides and P2 Receptors in Renal Function

Vallon, Volker; Unwin, Robert J.; Inscho, Edward W.; Leipziger, Jens; Kishore, Bellamkonda

doi:10.1152/physrev.00038.2018

Cited by 71 publications

(66 citation statements)

References 578 publications

(806 reference statements)

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“…Studies using combined techniques, such as selective antagonists, or tissue selective or global P2Y receptor subtype deficient mice, helped to elucidate the role of these receptors in most aspects of the cardiovascular system. Also, the role of P2YRs in renal function was recently reviewed (Vallon, Unwin, Inscho, Leipziger, & Kishore, 2019).…”

Section: P2y Receptors In the Cardiovascular Systemmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

180

184

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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Section: P2y Receptors In the Cardiovascular Systemmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

180

184

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Section: Discussionmentioning

confidence: 92%

“…Data implicate an important role for purinoceptors (P2 receptors) in controlling urinary Na + excretion [10,11]. P2 receptors are classified into ligandgated ion channels, P2X1-7, and G protein-coupled receptors, P2Y1,2,4,6,11-14 receptors [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Role for ovarian hormones in purinoceptor-dependent natriuresis

Gohar

Kasztan

Zhang

et al. 2020

Preprint

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Background: Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y 2 and P2Y 4 purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na + transport. Activation of these receptors inhibits epithelial Na + channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y 2 and P2Y 4 receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y 2 and P2Y 4 ) receptors regulating Na + excretion compared to male and OVX rats. Methods: To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na + excretion in anesthetized male, ovary-intact female and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y 2 and P2Y 4 receptors and (iii) mRNA expression of their downstream effectors (PLC-1d and ENaCa) in renal inner medullary tissues obtained from these three groups. We also subjectedcultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol(E 2 , 0, 10, 100 and 1000 nM) to test whether E 2 increases mRNA expression of P2Y 2 and P2Y 4 receptors. Results: Acute P2 inhibition attenuated urinary Na + excretion in ovary-intact females, but not in male or OVX rats.We found that P2Y 2 and P2Y 4 mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y 2 receptor protein abundance, compared to males, however, OVX did not eliminate this sex difference. We also found that E 2 dose-dependently upregulated P2Y 2 and P2Y 4 mRNA expression in mIMCD3. Conclusion: These data suggest that females have enhanced P2Y 2 and P2Y 4 -dependent regulation of Na + handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na + handling in premenopausal females.

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“…It has been shown that inhibiting P2 receptors rapidly enhances ENaC activity [16]. Experimental evidence documents the expression and functionality of P2Y 2 and P2Y 4 receptors in the collecting duct [11,13,16,40]. P2Y 2 knockout mice are hypertensive, possibly due to ENaC hyperactivity leading to enhanced renal Na + reabsorption [14,16].…”

Section: Discussionmentioning

confidence: 99%

Role for ovarian hormones in purinoceptor-dependent natriuresis

et al. 2020

Self Cite

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Background Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y2 and P2Y4 purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na+ transport. Activation of these receptors inhibits epithelial Na+ channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y2 and P2Y4 receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y2 and P2Y4) receptors regulating Na+ excretion compared to male and OVX rats. Methods To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na+ excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y2 and P2Y4 receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E2, 0, 10, 100, and 1000 nM) to test whether E2 increases mRNA expression of P2Y2 and P2Y4 receptors. Results Acute P2 inhibition attenuated urinary Na+ excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y2 and P2Y4 mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y2 receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E2 dose-dependently upregulated P2Y2 and P2Y4 mRNA expression in mIMCD3. Conclusion These data suggest that ovary-intact females have enhanced P2Y2 and P2Y4-dependent regulation of Na+ handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na+ handling in premenopausal females.

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Extracellular Nucleotides and P2 Receptors in Renal Function

Cited by 71 publications

References 578 publications

Update of P2Y receptor pharmacology: IUPHAR Review 27

Update of P2Y receptor pharmacology: IUPHAR Review 27

Role for ovarian hormones in purinoceptor-dependent natriuresis

Role for ovarian hormones in purinoceptor-dependent natriuresis

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