Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension

Gordienko, Dmitri; Povstyan, Oleksandr V.; Sukhanova, Khrystyna; Raphaël, Maylis; Harhun, Maksym I.; Dyskina, Yulia; Lehen’kyi, V’yacheslav; Jama, Abdirahman M.; Lu, Zhi-Liang; Skryma, Roman; Prevarskaya, Natalia

doi:10.1093/cvr/cvu249

Cited by 8 publications

(4 citation statements)

References 43 publications

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“…The REG AQP1 encodes a water-transporting protein in cell membranes of kidney proximal tubules and is involved in kidney development and injury responses (27). Two REGs (PLCB1 and ATP1A4) that are reportedly involved in hypertension or related organ damage participate in more than one of the mentioned pathways (28,29), in accordance with expectations of co-adaptation of the blood vesselheart-kidney axis in giraffe. In addition to genes in the mentioned pathways, we also detected other PSGs and REGs that may help to avoid hypertensive damage, including ANGPTL1, which is associated with the integrity of vascular endothelium (30), and TGFB1, which is strongly implicated in multiorgan fibrosis associated with hypertension (31).…”

Section: Adaptive Changes In Other Cardiovascular Genessupporting

confidence: 62%

A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe

et al. 2021

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The suite of adaptations associated with the extreme stature of the giraffe has long interested biologists and physiologists. By generating a high-quality chromosome-level giraffe genome and a comprehensive comparison with other ruminant genomes, we identified a robust catalog of giraffe-specific mutations. These are primarily related to cardiovascular, bone growth, vision, hearing, and circadian functions. Among them, the giraffe FGFRL1 gene is an outlier with seven unique amino acid substitutions not found in any other ruminant. Gene-edited mice with the giraffe-type FGFRL1 show exceptional hypertension resistance and higher bone mineral density, both of which are tightly connected with giraffe adaptations to high stature. Our results facilitate a deeper understanding of the molecular mechanism underpinning distinct giraffe traits, and may provide insights into the study of hypertension in humans.

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Section: Adaptive Changes In Other Cardiovascular Genessupporting

confidence: 62%

A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe

et al. 2021

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“…These data suggest that different causes of hypertension may have different effects on RyR function. There also may be regional differences, as increased expression of RyR2, increased Ca 2+ spark frequency and increased function of RyRs were found that contribute to purinergic P2X receptor-mediated Ca 2+ signaling in rat renal preglomerular arterial SMCs in SHR versus WKY (495). …”

Section: Ryanodine Receptorsmentioning

confidence: 99%

“…In renal preglomerular vascular SMCs, P2X receptor-induced IP 3 R-mediated Ca 2+ release is decreased in cells from SHR due to a decrease in the Ca 2+ load in the SR (495). This may account, in part, for the loss of preglomerular P2X receptor-mediated reactivity that is observed in hypertension.…”

Section: Inositol-145-triphosphate Receptorsmentioning

confidence: 99%

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

272

347

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Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes.

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“…For example, in Angiotensin-II mediated models of hypertension, there is an increase in vascular resistance causing a reduction in glomerular filtration rate. There is conflicting evidence regarding the expression of P2X1 following chronic administration of Angiotensin-II with some studies reporting an increase (Franco et al, 2011) and other studies reporting a reduction in P2X1 expression (Gordienko et al, 2015).…”

Section: P2x1 Receptormentioning

confidence: 99%

To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors?

et al. 2020

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The family of ligand-gated ion channels known as P2X receptors were discovered several decades ago. Since the cloning of the seven P2X receptors (P2X1-P2X7), a huge research effort has elucidated their roles in regulating a range of physiological and pathophysiological processes. Transgenic animals have been influential in understanding which P2X receptors could be new therapeutic targets for disease. Furthermore, understanding how inherited mutations can increase susceptibility to disorders and diseases has advanced this knowledge base. There has been an emphasis on the discovery and development of pharmacological tools to help dissect the individual roles of P2X receptors and the pharmaceutical industry has been involved in pushing forward clinical development of several lead compounds. During the discovery phase, a number of positive allosteric modulators have been described for P2X receptors and these have been useful in assigning physiological roles to receptors. This review will consider the major physiological roles of P2X1-P2X7 and discuss whether enhancement of P2X receptor activity would offer any therapeutic benefit. We will review what is known about identified compounds acting as positive allosteric modulators and the recent identification of drug binding pockets for such modulators.

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Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension

Cited by 8 publications

References 43 publications

A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe

A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors?

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