Sodium Transporters in Human Health and Disease

Sodium (Na+) electrochemical gradients established by Na+/K+ ATPase activity drives the transport of ions, minerals, and sugars in both excitable and non-excitable cells. Na+-dependent transporters can move these solutes in the same direction (cotransport) or in opposite directions (exchanger) across both the apical and basolateral plasma membranes of polarized epithelia. In addition to maintaining physiological homeostasis of these solutes, increases and decreases in sodium may also initiate, directly or indirectly, signaling cascades that regulate a variety of intracellular post-translational events. In this review, we will describe how the Na+/K+ ATPase maintains a Na+ gradient utilized by multiple sodium-dependent transport mechanisms to regulate glucose uptake, excitatory neurotransmitters, calcium signaling, acid-base balance, salt-wasting disorders, fluid volume, and magnesium transport. We will discuss how several Na+-dependent cotransporters and Na+-dependent exchangers have significant roles in human health and disease. Finally, we will discuss how each of these Na+-dependent transport mechanisms have either been shown or have the potential to use Na+ in a secondary role as a signaling molecule.

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Polarized targeting of V-ATPase in kidney epithelial cells.

Journal of Experimental Biology ◽

10.1242/jeb.172.1.231 ◽

1992 ◽

Vol 172 (1) ◽

pp. 231-243 ◽

Cited By ~ 6

Author(s):

D Brown ◽

I Sabolic ◽

S Gluck

Keyword(s):

B Cells ◽

Plasma Membranes ◽

Membrane Domains ◽

Intercalated Cells ◽

Acid Base Balance ◽

Acid Base ◽

A Cells ◽

Selective Targeting ◽

Base Balance ◽

Atpase Subunits

The membrane-associated V-ATPase that plays an important role in the regulation of acid-base balance by the kidney is a multisubunit enzyme that is densely packed into specialized membrane domains in intercalated cells. Intercalated cells can be separated into at least two subtypes, A-cells and B-cells, based on their morphological features, the distribution of V-ATPase, and the presence or absence of a basolateral chloride/bicarbonate anion exchanger (AE1) exclusively in B-cells. A-cells secrete protons into the tubule lumen, whereas B-cells secrete bicarbonate. The relative amounts of V-ATPase and AE1 in the plasma membranes of A- and B-cells are modulated under different acid-base conditions and provide a sensitive means by which urinary acidification can be controlled. The mechanisms governing the movement of acid-base transporting proteins between intracellular vesicles and the plasma membrane are under investigation. The microtubular apparatus of the cell is involved in maintaining both apical and basolateral polarity of the enzyme, and different isoforms of V-ATPase subunits may also be involved in the selective targeting of V-ATPase to different membrane domains.

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Mis-trafficking of bicarbonate transporters: implications to human diseasesThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o10-153 ◽

2011 ◽

Vol 89 (2) ◽

pp. 157-177 ◽

Cited By ~ 5

Author(s):

Ensaf Y. Almomani ◽

Carmen Y.S. Chu ◽

Emmanuelle Cordat

Keyword(s):

Peer Review Process ◽

Waste Product ◽

Gene Families ◽

Acid Base Balance ◽

Mammalian Cell Lines ◽

Current State ◽

Bicarbonate Transporters ◽

Base Balance ◽

Health And Disease ◽

Selection Of

Bicarbonate is a waste product of mitochondrial respiration and one of the main buffers in the human body. Thus, bicarbonate transporters play an essential role in maintaining acid-base balance but also during fetal development as they ensure tight regulation of cytosolic and extracellular environments. Bicarbonate transporters belong to two gene families, SLC4A and SLC26A. Proteins from these two families are widely expressed, and thus mutations in their genes result in various diseases that affect bones, pancreas, reproduction, brain, kidneys, eyes, heart, thyroid, red blood cells, and lungs. In this minireview, we discuss the current state of knowledge regarding the effect of SLC4A and SLC26A mutants, with a special emphasis on mutants that have been studied in mammalian cell lines and how they correlate with phenotypes observed in mice models.

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Na(+)-H+ exchange in choroid plexus and CSF in acute metabolic acidosis or alkalosis

AJP Renal Physiology ◽

10.1152/ajprenal.1990.258.6.f1528 ◽

1990 ◽

Vol 258 (6) ◽

pp. F1528-F1537 ◽

Cited By ~ 10

Author(s):

V. A. Murphy ◽

C. E. Johanson

Keyword(s):

Choroid Plexus ◽

Compartmental Analysis ◽

In Vivo Model ◽

Acid Base Balance ◽

Acid Base ◽

Adult Rats ◽

Choroidal Epithelium ◽

Base Balance ◽

Dependent Transport

Basolateral Na(+)-H+ exchange was analyzed with an in vivo model of choroid plexus (CP) epithelium in nephrectomized adult rats anesthetized with ketamine. Acid-base balance in blood was altered for 1 h over a pH continuum of 7.19 to 7.53 by equimolar intraperitoneal injections of HCl, NH4Cl, NaCl, or NaHCO3. Compartmental analysis enabled determination of CP intracellular pH (pHi) [dimethadione (DMO) method] and the choroid cellular concentration of 23Na (stable) and 22Na (tracer). HCl acidosis reduced the outwardly directed transmembrane basolateral H+ gradient, lowered the [23Na]i by 25%, and decreased the influx coefficient (Kin) for 22Na from blood into CP parenchyma (by 45% from 0.211 to 0.117 ml.g-1.h-1) and into cerebrospinal fluid (CSF) (by 43%, from 0.897 to 0.516). Compared with acid-loaded rats (HCl or NH4Cl), the NaHCO3-alkalotic animals had significantly enhanced uptake of 22Na into the CP-CSF system. This pH-dependent transport of Na+ from blood to CP was abolished by pretreatment with amiloride, an inhibitor of Na(+)-H+ exchange. Except in severe acidosis (HCl), the choroid cell pHi (7.05 +/- 0.02 in NaCl controls) and [HCO3-] (11-12 mM) remained stable in the face of acidemic and alkalemic challenges. With respect to reaction of the blood-CSF barrier to plasma acid-base perturbations, the responses of the fourth ventricle plexus pHi, [Na+]i, and 22Na uptake were similar to corresponding ones in lateral plexuses. We conclude that in the choroidal epithelium there is a Na(+)-H+ exchange activity capable of modulating Na+ flux into the CSF by approximately 50% as arterial pH is varied from 7.2 to 7.5.

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Modeling Transport and Flow Regulatory Mechanisms of the Kidney

ISRN Biomathematics ◽

10.5402/2012/170594 ◽

2012 ◽

Vol 2012 ◽

pp. 1-18 ◽

Cited By ~ 10

Author(s):

Anita T. Layton

Keyword(s):

Tubuloglomerular Feedback ◽

Regulatory Mechanisms ◽

Electrolyte Balance ◽

Acid Base Balance ◽

Acid Base ◽

Kidney Physiology ◽

Base Balance ◽

Modeling Transport ◽

Health And Disease ◽

Renal Oxygen

The kidney plays an indispensable role in the regulation of whole-organism water balance, electrolyte balance, and acid-base balance, and in the excretion of metabolic wastes and toxins. In this paper, we review representative mathematical models that have been developed to better understand kidney physiology and pathophysiology, including the regulation of glomerular filtration, the regulation of renal blood flow by means of the tubuloglomerular feedback mechanisms and of the myogenic mechanism, the urine concentrating mechanism, and regulation of renal oxygen transport. We discuss how such modeling efforts have significantly expanded our understanding of renal function in both health and disease.

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Respiratory Regulation of Acid-Base Balance in Health and Disease

Pulmonary Biology in Health and Disease ◽

10.1007/978-0-387-22435-0_15 ◽

2007 ◽

pp. 273-288

Author(s):

Eugene E. Nattie

Keyword(s):

Acid Base Balance ◽

Acid Base ◽

Respiratory Regulation ◽

Base Balance ◽

Health And Disease

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Higher Dietary Acidity is Associated with Lower Bone Mineral Density in Postmenopausal Iranian Women, Independent of Dietary Calcium Intake

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000207 ◽

2014 ◽

Vol 84 (3-4) ◽

pp. 0206-0217 ◽

Cited By ~ 8

Author(s):

Seyedeh-Elaheh Shariati-Bafghi ◽

Elaheh Nosrat-Mirshekarlou ◽

Mohsen Karamati ◽

Bahram Rashidkhani

Keyword(s):

Calcium Intake ◽

Dietary Calcium ◽

Dietary Calcium Intake ◽

Dietary Intakes ◽

Iranian Women ◽

Acid Base Balance ◽

Mineral Density ◽

Acid Base ◽

Base Balance ◽

Dietary Acid

Findings of studies on the link between dietary acid-base balance and bone mass are relatively mixed. We examined the association between dietary acid-base balance and bone mineral density (BMD) in a sample of Iranian women, hypothesizing that a higher dietary acidity would be inversely associated with BMD, even when dietary calcium intake is adequate. In this cross-sectional study, lumbar spine and femoral neck BMDs of 151 postmenopausal women aged 50 - 85 years were measured using dual-energy x-ray absorptiometry. Dietary intakes were assessed using a validated food frequency questionnaire. Renal net acid excretion (RNAE), an estimate of acid-base balance, was then calculated indirectly from the diet using the formulae of Remer (based on dietary intakes of protein, phosphorus, potassium, and magnesium; RNAERemer) and Frassetto (based on dietary intakes of protein and potassium; RNAEFrassetto), and was energy adjusted by the residual method. After adjusting for potential confounders, multivariable adjusted means of the lumbar spine BMD of women in the highest tertiles of RNAERemer and RNAEFrassetto were significantly lower than those in the lowest tertiles (for RNAERemer: mean difference -0.084 g/cm2; P=0.007 and for RNAEFrassetto: mean difference - 0.088 g/cm2; P=0.004). Similar results were observed in a subgroup analysis of subjects with dietary calcium intake of >800 mg/day. In conclusion, a higher RNAE (i. e. more dietary acidity), which is associated with greater intake of acid-generating foods and lower intake of alkali-generating foods, may be involved in deteriorating the bone health of postmenopausal Iranian women, even in the context of adequate dietary calcium intake.

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