scholarly journals Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3500
Author(s):  
Oriol Calvete ◽  
José Reyes ◽  
Hernán Valdés-Socin ◽  
Paloma Martin ◽  
Mónica Marazuela ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Neuroendocrine Tumors ◽  
Pathogenic Mechanism ◽  
Gastric Disease ◽  
Acid Base Balance ◽  
Acid Base ◽  
Internal Cell ◽  
Pathogenic Variants ◽  
Autoimmune Polyendocrine Syndrome

Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+ Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid–base imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panel with 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total, 64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients.

Regulation of urea synthesis by acid-base balance in vivo: role of NH3 concentration

1987 ◽  
Vol 252 (2) ◽  
pp. F221-F225 ◽  
Author(s):  
S. Cheema-Dhadli ◽  
R. L. Jungas ◽  
M. L. Halperin
Keyword(s):  
Ammonium Concentration ◽  
Urea Synthesis ◽  
Carbamoyl Phosphate ◽  
Acid Base Balance ◽  
Acid Base ◽  
Fixed Rate ◽  
Rate Limiting Step ◽  
Base Balance

The purpose of this study was to clarify how changes in acid-base balance influence the rate of urea synthesis in vivo. Since ureagenesis was increased by an ammonium infusion into rats, regulation seemed to be a function of the blood ammonium concentration. The rate of urea synthesis was constant at a fixed rate of ammonium infusion and independent of the conjugate base infused, chloride or bicarbonate. The steady-state blood ammonium concentration was higher in the rats that developed metabolic acidosis. Thus it appeared that regulation was not directly mediated by this ammonium concentration per se. The rate of urea synthesis was also independent of the blood pH. Accordingly, the rate of urea synthesis was examined as a function of the plasma NH3 concentration. The rate of ureagenesis was found to be directly proportional to the plasma NH3 concentration. Assuming that plasma NH3 levels reflect those in mitochondria, the NH3 concentration yielding half-maximal rates of urea synthesis (close to 2 microM) was in the same range as Km for the rate-limiting step in ureagenesis, carbamoyl phosphate synthetase (EC 6.3.4.16). These results suggest that, at a constant ammonium concentration, the decreased rate of ureagenesis caused by a pH fall in vitro could reflect an acidosis-induced decline in the concentration of true substrate (NH3) for this pathway.

Acid-base effects on ileal sodium chloride absorption in vitro

1988 ◽  
Vol 254 (3) ◽  
pp. G329-G333 ◽  
Author(s):  
S. G. Vaccarezza ◽  
A. N. Charney
Keyword(s):  
Sodium Chloride ◽  
Sodium Absorption ◽  
Bathing Solution ◽  
Acid Base Balance ◽  
Acid Base ◽  
Solution Ph ◽  
Ussing Chambers ◽  
Hepes Buffer ◽  
Chloride Absorption

Previous work from this laboratory has shown that in the intact animal, ileal sodium chloride absorption is responsive to alterations in systemic acid-base balance. In vitro studies were undertaken to determine the nature of the active transport process affected. Paired, unstripped ileal tissues from Sprague-Dawley rats were mounted in modified Ussing chambers, and unidirectional 22Na and 36Cl fluxes were measured under short-circuited conditions (Isc). Acid-base effects were examined by changing either bathing solution partial pressure of CO2 (PCO2) or HCO3 concentration or by the addition of HCl or NaOH to a non-HCO3 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffer. When pH was decreased from 7.6 to 7.1, net sodium absorption increased twofold regardless of the means by which pH was changed. This increase was primarily accounted for by an increase in mucosal-to-serosal flux. Net chloride absorption was affected in a similar way, but the increase in absorption was primarily accounted for by an increase in mucosal-to-serosal flux only in the HEPES buffer. These changes were accompanied by reductions in Isc and residual flux. When all groups were considered, mucosal-to-serosal Na (JNam----s) and net Na (JNanet) fluxes correlated strongly with bathing solution pH (r = 0.84 and 0.94, respectively, P less than 0.01). These data indicate that an active ileal sodium chloride absorptive process is specifically responsive to changes in bathing solution pH. In addition, pH may affect ileal electrogenic chloride, HCO3, and/or H secretion.

An Approach to the Problems of Acid-Base Balance

1970 ◽  
Vol 39 (2) ◽  
pp. 169-182 ◽  
Author(s):  
C. T. Kappagoda ◽  
R. J. Linden ◽  
H. M. Snow
Keyword(s):  
Sodium Bicarbonate ◽  
Respiratory Acidosis ◽  
Acid Base Balance ◽  
Acid Base ◽  
Titration Curves ◽  
Base Parameters ◽  
Base Balance ◽  
Acid Base Disturbance ◽  
Direct Extrapolation

1. The existing methods for assessing states of acidosis are discussed with particular reference to non-respiratory acidosis. Most of these methods are based either on the Henderson—Hasselbalch equation or on the direct extrapolation of in vitro studies on blood to the whole animal. The evidence available shows that these methods cannot be used to obtain an accurate assessment of disturbances of acid-base balance in the whole animal. 2. The experiments were designed to investigate the acid-base parameters of an animal when a respiratory acidosis was superimposed on a non-respiratory acidosis caused by the infusion of n HCl; from these experiments it was possible to construct CO2 titration curves at various levels of non-respiratory acidosis. 3. A scheme which is based upon the CO2 titration curves, has been proposed for assessing an acute acid-base disturbance in terms of its respiratory and non-respiratory components. 4. The use of sodium bicarbonate to correct a non-respiratory acidosis was investigated, and it was shown that the amount of sodium bicarbonate required varied with the rate of infusion. No firm predictions could be made regarding the dose of bicarbonate required, but from the results of the present experiments an infusion rate of 0·1 mEq kg−1 min−1 is recommended in dogs.

scholarly journals pH-dependent regulation of the α-subunit of H+-K+-ATPase (HKα2)

2011 ◽  
Vol 301 (3) ◽  
pp. F536-F543 ◽  
Author(s):  
Juan Codina ◽  
Timothy S. Opyd ◽  
Zachary B. Powell ◽  
Cristina M. Furdui ◽  
Snezana Petrovic ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Immunoblot Analysis ◽  
Acid Base Balance ◽  
Acid Base ◽  
Membrane Expression ◽  
Α Subunit ◽  
Hek 293 ◽  
Genetic Ablation ◽  
Base Balance

The H+-K+-ATPase α-subunit (HKα2) participates importantly in systemic acid-base homeostasis and defends against metabolic acidosis. We have previously shown that HKα2 plasma membrane expression is regulated by PKA (Codina J, Liu J, Bleyer AJ, Penn RB, DuBose TD Jr. J Am Soc Nephrol 17: 1833–1840, 2006) and in a separate study demonstrated that genetic ablation of the proton-sensing Gs-coupled receptor GPR4 results in spontaneous metabolic acidosis (Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, Petrovic S. J Am Soc Nephrol 21: 1745–1755, 2010). In the present study, we investigated the ability of chronic acidosis and GPR4 to regulate HKα2 expression in HEK-293 cells. Chronic acidosis was modeled in vitro by using multiple methods: reducing media pH by adjusting bicarbonate concentration, adding HCl, or by increasing the ambient concentration of CO2. PKA activity and HKα2 protein were monitored by immunoblot analysis, and HKα2 mRNA, by real-time PCR. Chronic acidosis did not alter the expression of HKα2 mRNA; however, PKA activity and HKα2 protein abundance increased when media pH decreased from 7.4 to 6.8. Furthermore, this increase was independent of the method used to create chronic acidosis. Heterologous expression of GPR4 was sufficient to increase both basal and acid-stimulated PKA activity and similarly increase basal and acid-stimulated HKα2 expression. Collectively, these results suggest that chronic acidosis and GPR4 increase HKα2 protein by increasing PKA activity without altering HKα2 mRNA abundance, implicating a regulatory role of pH-activated GPR4 in homeostatic regulation of HKα2 and acid-base balance.

Responses to Hypersaline Exposure in the Euryhaline Crayfish Pacifastacus Leniusculus: I. The Interaction between Ionic and Acid-base Regulation

1982 ◽  
Vol 99 (1) ◽  
pp. 425-445
Author(s):  
MICHÈLE G. WHEATLY ◽  
B. R. MCMAHON
Keyword(s):  
Carbonic Acid ◽  
Sea Water ◽  
Inorganic Ions ◽  
Pacifastacus Leniusculus ◽  
Acid Base Balance ◽  
Acid Base ◽  
Salinity Acclimation ◽  
Base Balance ◽  
Hypocapnic Alkalosis

Haemolymph iono- and osmoregulation and acid-base balance were recorded after 48 h exposure at 15 °C to a range of increasing ambient salinities (0, 25, 50 and 75% sea water) in the euryhaline crayfish Pacifastacus leniusculus (Dana). Except for K+, concentrations of all measured inorganic ions and osmolality were significantly elevated in 50 and 75% SW. When compared with ambient changes there was evidence of a transition from hyperto hypoionic regulation above 44% SW. Ca2+ was regulated for a constant blood-medium difference. A progressive reduction in total CO2 was recorded; pH was maintained except in 75% SW where a haemolymph acidosis developed. To permit calculation of CO2 tension (PCOCO2), carbon dioxide solubility coefficient (αCO2) and the apparent first dissociation constant of carbonic acid (p K'1) were experimentally determined in vitro. αCO2 decreased progressively with acclimation salinity but was unaffected by circulating protein. pK'1 decreased as a function both of physiological pH and increasing haemolymph ionic strength. PCOCO2 calculated using these empirical constants, progressively decreased with high-salinity acclimation. The resulting ‘hypocapnic alkalosis’ was partially offset by a metabolic acidosis, whose correlation with extracellular anisosmotic and intracellular isosmotic regulation is discussed.

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

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0206-0217 ◽  
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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