title: Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  We compared the expression of pertinent genes and P2XR-linked Ca(2+) entry and Ca(2+) 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 Ca(2+) entry and Ca(2+) 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 Ca(2+) load. The SR Ca(2+) load reduction is caused by attenuated Ca(2+) uptake via down-regulated sarco-/endoplasmic reticulum Ca(2+)-ATPase 2b and elevated Ca(2+) leak from the SR via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors. Spontaneous activity of these Ca(2+)-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.
authors.affiliation: INSERM U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université des Sciences et Technologies de Lille, Batiment SN3, Villeneuve d'Ascq 59655, France Laboratory of Molecular Pharmacology and Biophysics of Cell Signaling, Bogomoletz Institute of Physiology, Kiev, Ukraine gordienkdv@gmail.com dvg@biph.kiev.ua.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Gordienko
authors.affiliation: Laboratory of Molecular Pharmacology and Biophysics of Cell Signaling, Bogomoletz Institute of Physiology, Kiev, Ukraine Division of Basic Medical Sciences, St. George's, University of London, London, UK.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Povstyan
authors.affiliation: Laboratory of Molecular Pharmacology and Biophysics of Cell Signaling, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: Khrystyna
authors.initials: K
authors.lastname: Sukhanova
authors.affiliation: INSERM U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université des Sciences et Technologies de Lille, Batiment SN3, Villeneuve d'Ascq 59655, France.
authors.forename: Maylis
authors.initials: M
authors.lastname: Raphaël
authors.affiliation: Laboratory of Molecular Pharmacology and Biophysics of Cell Signaling, Bogomoletz Institute of Physiology, Kiev, Ukraine Division of Basic Medical Sciences, St. George's, University of London, London, UK.
authors.forename: Maksym
authors.initials: M
authors.lastname: Harhun
authors.affiliation: Laboratory of Molecular Pharmacology and Biophysics of Cell Signaling, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Dyskina
authors.affiliation: INSERM U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université des Sciences et Technologies de Lille, Batiment SN3, Villeneuve d'Ascq 59655, France.
authors.forename: V'yacheslav
authors.initials: V
authors.lastname: Lehen'kyi
authors.affiliation: MRC, Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Abdirahman
authors.initials: A
authors.lastname: Jama
authors.affiliation: MRC, Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Lu
authors.affiliation: INSERM U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université des Sciences et Technologies de Lille, Batiment SN3, Villeneuve d'Ascq 59655, France.
authors.forename: Roman
authors.initials: R
authors.lastname: Skryma
authors.affiliation: INSERM U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université des Sciences et Technologies de Lille, Batiment SN3, Villeneuve d'Ascq 59655, France.
authors.forename: Natalia
authors.initials: N
authors.lastname: Prevarskaya
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D008297:Male; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D058469:Receptors, Purinergic P2X / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015220:Calcium Channels; D058469:Receptors, Purinergic P2X
keywords: Calcium signalling; Gene expression; Hypertension; P2X receptors; Renal vascular myocytes