Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension

Handle URI:
http://hdl.handle.net/10754/566122
Title:
Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension
Authors:
Gordienko, Dmitri V.; Povstyan, Oleksandr V.; Sukhanova, Khrystyna Yu; Raphaël, Maylis; Harhun, Maksym I.; Dyskina, Yulia; Lehen'Kyi, V'Yacheslav; Jama, Abdirahman Mahmoud ( 0000-0001-6107-9734 ) ; Lu, Zhiliang; Skryma, Roman N.; Prevarskaya, Natalia B.
Abstract:
Aims P2X receptors (P2XRs) mediate sympathetic control and autoregulation of renal circulation triggering preglomerular vasoconstriction, which protects glomeruli from elevated pressures. Although previous studies established a casual link between glomerular susceptibility to hypertensive injury and decreased preglomerular vascular reactivity to P2XR activation, the mechanisms of attenuation of the P2XR signalling in hypertension remained unknown. We aimed to analyse molecular mechanisms of the impairment of P2XR signalling in renal vascular smooth muscle cells (RVSMCs) in genetic hypertension. Methods and results We compared the expression of pertinent genes and P2XR-linked Ca2+ entry and Ca2+ release mechanisms in RVSMCs of spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar Kyoto (WKY) rats. We found that, in SHR RVSMCs, P2XR-linked Ca2+ entry and Ca2+ release from the sarcoplasmic reticulum (SR) are both significantly reduced. The former is due to down-regulation of the P2X1 subunit. The latter is caused by a decrease of the SR Ca2+ load. The SR Ca2+ load reduction is caused by attenuated Ca2+ uptake via down-regulated sarco-/endoplasmic reticulum Ca2+-ATPase 2b and elevated Ca2+ leak from the SR via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors. Spontaneous activity of these Ca2+-release channels is augmented due to up-regulation of RyR type 2 and elevated IP3 production by up-regulated phospholipase C-β1. Conclusions Our study unravels the cellular and molecular mechanisms of attenuation of P2XR-mediated preglomerular vasoconstriction that elevates glomerular susceptibility to harmful hypertensive pressures. This provides an important impetus towards understanding of the pathology of hypertensive renal injury.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program
Publisher:
Oxford University Press (OUP)
Journal:
Cardiovascular Research
Issue Date:
16-Dec-2014
DOI:
10.1093/cvr/cvu249
Type:
Article
ISSN:
00086363
Appears in Collections:
Articles; Bioscience Program; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorGordienko, Dmitri V.en
dc.contributor.authorPovstyan, Oleksandr V.en
dc.contributor.authorSukhanova, Khrystyna Yuen
dc.contributor.authorRaphaël, Maylisen
dc.contributor.authorHarhun, Maksym I.en
dc.contributor.authorDyskina, Yuliaen
dc.contributor.authorLehen'Kyi, V'Yacheslaven
dc.contributor.authorJama, Abdirahman Mahmouden
dc.contributor.authorLu, Zhiliangen
dc.contributor.authorSkryma, Roman N.en
dc.contributor.authorPrevarskaya, Natalia B.en
dc.date.accessioned2015-08-12T09:29:11Zen
dc.date.available2015-08-12T09:29:11Zen
dc.date.issued2014-12-16en
dc.identifier.issn00086363en
dc.identifier.doi10.1093/cvr/cvu249en
dc.identifier.urihttp://hdl.handle.net/10754/566122en
dc.description.abstractAims P2X receptors (P2XRs) mediate sympathetic control and autoregulation of renal circulation triggering preglomerular vasoconstriction, which protects glomeruli from elevated pressures. Although previous studies established a casual link between glomerular susceptibility to hypertensive injury and decreased preglomerular vascular reactivity to P2XR activation, the mechanisms of attenuation of the P2XR signalling in hypertension remained unknown. We aimed to analyse molecular mechanisms of the impairment of P2XR signalling in renal vascular smooth muscle cells (RVSMCs) in genetic hypertension. Methods and results We compared the expression of pertinent genes and P2XR-linked Ca2+ entry and Ca2+ release mechanisms in RVSMCs of spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar Kyoto (WKY) rats. We found that, in SHR RVSMCs, P2XR-linked Ca2+ entry and Ca2+ release from the sarcoplasmic reticulum (SR) are both significantly reduced. The former is due to down-regulation of the P2X1 subunit. The latter is caused by a decrease of the SR Ca2+ load. The SR Ca2+ load reduction is caused by attenuated Ca2+ uptake via down-regulated sarco-/endoplasmic reticulum Ca2+-ATPase 2b and elevated Ca2+ leak from the SR via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors. Spontaneous activity of these Ca2+-release channels is augmented due to up-regulation of RyR type 2 and elevated IP3 production by up-regulated phospholipase C-β1. Conclusions Our study unravels the cellular and molecular mechanisms of attenuation of P2XR-mediated preglomerular vasoconstriction that elevates glomerular susceptibility to harmful hypertensive pressures. This provides an important impetus towards understanding of the pathology of hypertensive renal injury.en
dc.publisherOxford University Press (OUP)en
dc.subjectCalcium signallingen
dc.subjectGene expressionen
dc.subjectHypertensionen
dc.subjectP2X receptorsen
dc.subjectRenal vascular myocytesen
dc.titleImpaired P2X signalling pathways in renal microvascular myocytes in genetic hypertensionen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentBioscience Programen
dc.identifier.journalCardiovascular Researchen
kaust.authorJama, Abdirahman Mahmouden
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