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Clues and new evidences in arterial hypertension: unmasking the role of the chloride anion

  • Invited Review
  • Published:
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Abstract

The present review will focus on the role of chloride anion in cardiovascular disease, with special emphasis in the development of hypertensive disease and vascular inflammation. It is known that acute and chronic overload of sodium chloride increase blood pressure and have pro-inflammatory and pro-fibrotic effects on different target organs, but it is unknown how chloride may influence these processes. Chloride anion is the predominant anion in the extracellular fluid and its intracellular concentration is dynamically regulated. As the queen of the electrolytes, it is of crucial importance to understand the physiological mechanisms that regulate the cellular handling of this anion including the different transporters and cellular chloride channels, which exert a variety of functions, such as regulation of cellular proliferation, differentiation, migration, apoptosis, intracellular pH and cellular redox state. In this article, we will also review the relationship between dietary, serum and intracellular chloride and how these different sources of chloride in the organism are affected in hypertension and their impact on cardiovascular disease. Additionally, we will discuss the approach of potential strategies that affect chloride handling and its potential effect on cardiovascular system, including pharmacological blockade of chloride channels and non-pharmacological interventions by replacing chloride by another anion.

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Abbreviations

9-AC:

9-Anthracene- carboxylic acid

ANG II:

Angiotensin II

BSND:

Bartter syndrome with sensorineural deafness (Barttin)

CaCCs:

Calcium-activated chloride channels

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

CBS:

Cystathionine-β-synthase

CFTR:

Cystic fibrosis transmembrane conductance regulator

Cl :

Chloride

ClCs:

Chloride channel family

ClC-1:

Chloride channel subtype 1

ClC-2:

Chloride channel subtype 2

ClC-3:

Chloride channel subtype 3

ClC-4:

Chloride channel subtype 4

ClC-5:

Chloride channel subtype 5

ClC-6:

Chloride channel subtype 6

ClC-7:

Chloride channel subtype 7

ClC-Ka:

Chloride channel-kidney subtype a

ClC-Kb:

Chloride channel-kidney subtype b

CLIC:

Chloride intracellular channels

ClVR:

Chloride volume-regulated channel

CPP:

P-Chlorophenoxy-propionic acid

Dahl-R:

Dahl salt-resistant rats

Dahl-S:

Dahl salt-sensitive rats

DCT:

Distal convoluted tubule

DIDS:

4,4′-Diisothiocyanostilbene-2,2′-disulfonic acid

DOCA:

Desoxycorticosterone acetate

DOCP:

Desoxycorticosterone pivalate

dp/dt:

Ratio of pressure change in the ventricular cavity during the isovolemic contraction period

eNOS :

Endothelial nitric oxide synthase

ERK a/b:

Extracellular signal-regulated kinases

GABAAR:

Gamma-aminobutyric acid type A receptors

GDNF:

Glial cell line-derived neurotrophic growth factor

H2O2 :

Hydrogen peroxide

HCTZ:

Hydrochlorothiazide

HOCl:

Hypochlorous acid

IL:

Interleukin

K+ :

Potassium

K3C6H5O7 :

Potassium citrate

KCC2:

K+-Cl cotransporter 2

KCl:

Potassium chloride

KHCO3 :

Potassium bicarbonate

MCT:

Monocarboxylate transporter family

MPS:

Mononuclear phagocyte system

Na+ :

Sodium

Na3C6H5O7 :

Sodium citrate

NaCl:

Sodium chloride

NaHCO3 :

Sodium bicarbonate

NF-kB:

Nuclear transcription factor kappa beta

NFA:

4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid

NKCC2:

Na+/2Cl/K+ cotransporter

NO:

Nitric oxide

NOX:

NADPH oxidase

O2 •− :

Superoxide anion

OH :

Hydroxyl radicals

ONOO :

Peroxynitrite

PGE2 :

Prostaglandin E2

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

PP :

Serine-threonine protein phosphatases

RAS :

Renin angiotensin system

RNS :

Reactive nitrogen species

ROMK1 :

Rectifying potassium channel

ROS :

Reactive oxygen species

SHR :

Spontaneously hypertensive rats

SHR-S:

Spontaneously hypertensive rats salt sensitive

SHRSP:

Spontaneously hypertensive rats stroke prone

SM :

Smooth muscle

SNPs :

Single nucleotide polymorphisms

SOD:

Superoxide dismutase

SV/PP :

Stroke volume/pulse pressure ratio

tAL :

Thin ascending limb

TAL:

Thick ascending limb

TgB1-hPDS:

Transgenic mice overexpressing the chloride transporter pendrin in intercalated cells

TMEM16A:

Transmembrane protein with unknown function 16

TNF-α :

Tumour necrosis factor alpha

TONEBP :

Tonicity-responsive enhancer-binding protein

TPR :

Total peripheral resistance

VEGFC:

Vascular endothelial growth factor C

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Funding

This work was supported by grants from the ANPCYT (PICT 2018–01105), Universidad de Buenos Aires (UBACYT 20020170100621BA), Sociedad Argentina de Hipertensión Arterial (Stimulus Grant for Research on Hypertension 2018) and Instituto Universitario de Ciencias de la Salud, Fundación Héctor A. Barceló (BA-Med-039–2017).

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Kouyoumdzian, N.M., Kim, G., Rudi, M.J. et al. Clues and new evidences in arterial hypertension: unmasking the role of the chloride anion. Pflugers Arch - Eur J Physiol 474, 155–176 (2022). https://doi.org/10.1007/s00424-021-02649-5

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