Bicarbonate Absorption Research Articles

Thermo-electrocatalytic reduction of potassium bicarbonate to formate on an indium electrode

Abstract In this work, we developed a thermo-electrochemical bicarbonate reduction (TEBR) process for the production of formate on a simple indium foil electrode. The TEBR process relies on the synergistic effect of thermochemical and electrochemical processes, which ensures the continuous redox of metals on the electrode surface. In the thermochemical environment, indium can interact with water to form InO(OH), which facilitates the absorption and hydrogenation of bicarbonate to form formate. In the electrochemical environment, the reduction of indium oxide to indium supports the maintenance of a dynamic interface of In3+/In. This study revealed that, when an indium electrode is employed in the reaction system, the Faraday efficiency and partial current density of formate can reach 86.2% and 86.5 mA cm−2, respectively, at 100 °C with a KHCO3 concentration of 3.0 mol L−1. Therefore, an indium electrode can be effectively employed for the direct reduction of bicarbonate to produce formate. This study provides an insight into the synergistic effect of thermochemical and electrochemical processes, and suggests a potential application of indium in the production of formate via a TEBR process.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

Metabolic alkalosis in infants treated with peritoneal dialysis.

Acid-base balance is maintained by kidney excretion of titratable acids and bicarbonate reabsorption. Metabolic alkalosis is uncommon in dialysis-treated patients. The aim of this retrospective study was to assess the rate of metabolic alkalosis in pediatric patients treated with peritoneal dialysis. Medical records of children treated with peritoneal dialysis in Shaare Zedek Medical Center from January 2000 to June 2021 were reviewed and compared with young adults currently treated with peritoneal dialysis. Demographic, clinical, and peritoneal dialysis characteristics were extracted from the medical records. Thirty chronic peritoneal dialysis patients were included in our study, seven under 2 years, 13 between 2 and 18 years, and 10 adults. 90.3% of the measurements in infants showed metabolic alkalosis compared to 32.3% in the 2-18-year group and none in the adult group. Higher size-adjusted daily exchange volume, lack of urine output, and high lactate-containing dialysate were associated with metabolic alkalosis. Alkalosis was not explained by vomiting, diuretic therapy, or carbonate-containing medications. High transport membrane, low dietary protein, and malnutrition, all previously reported explanations for metabolic alkalosis, were not found in our study. Metabolic alkalosis is common in infants treated with peritoneal dialysis as opposed to older children and adults. High lactate-containing dialysate is a possible explanation. Higher size-adjusted daily dialysate exchange volume, which may reflect higher bicarbonate absorption, is another independent predictor of alkalosis. Acid-base status should be closely followed in infants, and using a dialysis solution with lower bicarbonate or lactate level should be considered. A higher resolution version of the graphical abstract is available as Supplementary Information.

Hypokalaemia in Type-4 Renal Tubular Acidosis: A Rare Presentation

Proximal/Type-2 Renal Tubular Acidosis (RTA) occurs due to impairment of bicarbonate absorption in the proximal tubule and is mainly characterised by hypokalaemia and metabolic acidosis. There are various causes of proximal RTA like genetic, cystinosis, Wilson’s disease, drugs and toxins, vitamin D deficiency, hyperparathyroidism, amyloidosis. Vitamin D deficiency is one of the uncommon causes and is more common in elderly. Hereby, authors present a case report of a diabetic and hypothyroid 30-year-old female, who presented with chronic limb weakness, myalgia and bilateral leg swelling. After detailed history taking, clinical examination and laboratory investigations, she was diagnosed with nephrotic syndrome and proximal RTA associated with vitamin D deficiency. She had hypokalaemia with acidosis initially and was managed with diuretics, Angiotensin Converting Enzyme (ACE) inhibitors, vitamin D and potassium supplementation, after which, she developed hyperkalaemia with acidosis. She was evaluated for hyperkalaemic RTA and its common causes and was diagnosed with hyperkalaemic RTA associated with diabetes. Thus, treatment of type-2 RTA due to vitamin D deficiency, led to unmasking of underlying type-4 RTA due to diabetic nephropathy.

Activated Charcoal and Bicarbonate for Aspirin Toxicity: a Retrospective Series.

Aspirin overdose causes acid-base disturbances and organ dysfunction. Management is guided by research reported over 50years ago when chronic aspirin toxicity was common and accounted for significant morbidity. We investigate our experience of aspirin overdose and the effectiveness of charcoal and bicarbonate administration over 20years. This is a retrospective series of acute aspirin overdosefrom two toxicology units from January 2000 to September 2019. Acute aspirin ingestions > 3000mg were identified in each unit's database. Excluded were cases of chronic exposure, hospital presentation > 24 hours after ingestion, and cases without a salicylate concentration. Included in our analysis wasdemographic data, clinical effects, investigations, complications, and treatment. There were 132 presentations in 108 patients (79 females (73%)). The median age was 28years (range: 13-93years). The median dose ingested was 7750mg (IQR: 6000-14,400mg). There were 44 aspirin-only ingestions. Mild toxicity (nausea, vomiting, tinnitus or hyperventilation) occurred in 22 with a median dose of 160mg/kg. Moderate toxicity (acid-base disturbance, confusion) occurred in 16 with a median ingested dose of 297mg/kg. There were no cases of severe toxicity (coma or seizures) due to aspirin alone. The median peak salicylate concentration was 276mg/L (IQR: 175-400mg/L, range: 14-814mg/L). There was a moderate association between dose ingested and peak concentration (Pearson r = 0.58; 95% CI 0.45-0.68). Activated charcoal was administered in 36 (27%) cases, which decreased the median peak salicylate concentration (34.2 to 24.8mg/L/g (difference: 9.4, 95% CI: 1.0-13.1)). Bicarbonate was administered in 34 (26%) presentations, decreasing the median apparent elimination half-life from 13.4 to 9.3h (difference: 4.2h, 95% CI: 1.0-6.5h). Acute aspirin overdose caused only mild to moderate effects in this series. Early administration of activated charcoal decreased absorption and use ofbicarbonate enhancedelimination.

Photosynthetic responses of Halimeda scabra (Chlorophyta, Bryopsidales) to interactive effects of temperature, pH, and nutrients and its carbon pathways.

In this study, we evaluated the interactive effects of temperature, pH, and nutrients on photosynthetic performance in the calcareous tropical macroalga Halimeda scabra. A significant interaction among these factors on gross photosynthesis (Pgross) was found. The highest values of Pgross were reached at the highest temperature, pH, and nutrient enrichment tested and similarly in the control treatment (no added nutrients) at 33 °C at the lowest pH. The Q10 Pgross values confirmed the effect of temperature only under nutrient enrichment scenarios. Besides the above, bicarbonate (HCO3−) absorption was assessed by the content of carbon stable isotope (δ13C) in algae tissue and by its incorporation into photosynthetic products, as well as by carbonic anhydrase (CA) inhibitors (Acetazolamide, AZ and Ethoxyzolamide, EZ) assays. The labeling of δ13C revealed this species uses both, CO2 and HCO3− forms of Ci relying on a CO2 Concentration Mechanism (CCM). These results were validated by the EZ-AZ inhibition assays in which photosynthesis inhibition was observed, indicating the action of internal CA, whereas AZ inhibitor did not affect maximum photosynthesis (Pmax). The incorporation of 13C isotope into aspartate in light and dark treatments also confirmed photosynthetic and non-photosynthetic the HCO3−uptake.

Lipopolysaccharide directly inhibits bicarbonate absorption by the renal outer medullary collecting duct

Acidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. We examined the effect of lipopolysaccharide (LPS), on HCO3 absorption in isolated perfused rabbit OMCDi. LPS caused a ~ 40% decrease in HCO3 absorption, providing a mechanism for E. coli pyelonephritis-induced acidosis. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and Wortmannin, a phosphoinositide 3-kinase inhibitor, prevented the LPS-mediated decrease, demonstrating the role of TLR4-PI3-kinase signaling and providing proof-of-concept for therapeutic interventions aimed at ameliorating OMCDi dysfunction and pyelonephritis-induced acidosis.

Milling and baking quality of hexaploid spring wheat starch synthase IIa (ssIIa) mutants with elevated amylose content

AbstractBackground and objectivesNovel alleles of starch synthase II (ssIIa) homeologs were created in a soft white spring wheat using chemical mutagenesis and then combined to create four unique ssIIa triple mutant haplotypes. Previous research found the resultant triple ssIIa mutants were hard in texture and had increased seed amylose and protein content that was strongly correlated with decreases in individual seed weight and seed starch content. The objective of this research was to examine how these changes in amylose content affect milling and bread baking characteristics.FindingsTriple ssIIa mutant haplotypes yielded significantly less flour that had a higher protein and ash content, decreased brightness, and increased yellowness and redness compared to controls. Solvent retention capacity tests on flour from ssIIa mutant lines had significant increases in water, sucrose, and sodium bicarbonate absorption but similar lactic acid absorption and poor gluten performance indexes compared to controls. Flour dough made from ssIIa mutants had increased water absorption with increased mixing tolerance and produced bread with significantly reduced loaf volume, crumb grain score, and crumb brightness with increased crumb yellowness and redness. Attempts to restore loaf volume using up to 6% vital wheat gluten were unsuccessful.ConclusionsHigh amylose ssIIa triple mutants have significant decreases in flour yields as a result of their diminished starch content and seed size. The unique composition of flour from ssIIa triple mutants does not readily lend itself to producing a functional dough for bread making and resultant bread has significant decreases in loaf volume.Significance and noveltyOur results demonstrate that flour with increased amylose levels can be used to create bread with increased protein and dietary fiber.

69-Year-Old Woman With Confusion and Fatigue

Resident in Internal Medicine, Mayo School of Graduate Medical Education, Rochester, MN (H.M.K.); Advisor to resident and Consultant in Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN (A.E.K.). A 69-year-old woman presented to her primary care physicianwith a 4-day history of fatigue and dizziness. She was 45 minutes late for her appointment because she had trouble driving to the office. She reported no motor or sensory deficits but had difficulty with coordination. Review of systems was positive for dysuria and urinary frequency. She did not have fever, chills, weight or appetite changes, respiratory, cardiac, or gastrointestinal symptoms, or recent head trauma. The patient’s medical history was remarkable for hypertension, hyperlipidemia, type 2 diabetes mellitus, osteoporosis, and gastroesophageal reflux disease. Medications included metoprolol tartrate, lisinopril with hydrochlorothiazide, lovastatin, cholecalciferol, and as-needed calcium carbonate. She had smoked half a pack of cigarettes per day for 40 years but had quit smoking 6 years previously. She didnot use alcohol or illicit drugs. On examination, the patient was afebrile with a blood pressure of 104/67 mm Hg, heart rate of 76 beats/min, respiratory rate of 17 breaths/min, oxygen saturation of 94% while breathing room air, and body mass index (calculated as weight in kilograms divided by height inmeters squared) of 39 kg/m. Shewas alert and oriented to person, place, and time. Her speech was dysarthric, and she had difficulty following simple commands. Her coordination was impaired with symmetric dysmetria on finger-to-nose testing, heel-kneeshin testing, and rapid alternating movements. Cranial nerves II through XII were intact. Results of motor and sensory examinations were within normal limits. Reflexes were symmetric. Lymph node, thyroid, cardiac, respiratory, gastrointestinal, musculoskeletal, and skin examinations identified no abnormalities.

Structural Differences in Respiratory System and Airway of Parturients

Oxygen consumption increases with increased alveolar ventilation and respiratory alkalosis occurs. Thus, PaCO2 becomes 28-32 mmHg in pregnant women, and this amount is compensated with renal bicarbonate absorption. Preoxygenation can be made slower by inhalation of 100% oxygen for 2-5 minutes. Denitrogenation of the lungs occurs after three minutes [11. Baraka AS, Taha SK, Aouad MT, El-Khatib MF, Kawkabani NI (1999) Preoxygenation: comparison of maximal breathing and tidal volume breathing techniques. Anesthesiology 91: 612-616.]. Another method can be applied quickly with 4-8 deep breaths of 100% oxygen [22. Benumof JL (1999) Preoxygenation: best method for both efficacy and efficiency. Anesthesiology 91: 603-605.]. However, for pregnant women who will have a cesarean section under general anesthesia, an oxygen fraction of 1 has been shown to increase fetal oxygenation more compared with the 0.3 or 0.5 FiO2 [33. Khaw KS, Ngan Kee WD, Chu CY, Ng FF, Tam WH, et al. (2010) Effects of different inspired oxygen fractions on lipid peroxidation during general anaesthesia for elective Caesarean section. Br J Anaesth 105: 355-360. ]. As this may lead to free oxygen radicals and apsorbtion atalectesia, 80 % oxygen is recommended.

Toward rational design of amines for CO2 capture: Substituent effect on kinetic process for the reaction of monoethanolamine with CO2

Amines have been considered as promising candidates for post-combustion CO2 capture. A mechanistic understanding for the chemical processes involved in the capture and release of CO2 is important for the rational design of amines. In this study, the structural effects of amines on the kinetic competition among three typical products (carbamates, carbamic acids and bicarbonate) from amines+CO2 were investigated, in contrast to previous thermodynamic studies to tune the reaction of amines with CO2 based on desirable reaction enthalpy and reaction stoichiometry. We used a quantum chemical method to calculate the activation energies (Ea) for the reactions of a range of substituted monoethanolamines with CO2 covering three pathways to the three products. The results indicate that the formation of carbamates is the most favorable, among the three considered products. In addition, we found that the Ea values for all pathways linearly correlate with pKa of amines, and more importantly, the kinetic competition between carbamate and bicarbonate absorption pathways varies with pKa of the amines, i.e. stronger basicity results in less difference in Ea. These results highlight the importance of the consideration of kinetic competition among different reaction pathways in amine design.

The Strategy of Sustainable Agricultural Development, Identifying and Zoning Certain Indices of Environmental Pollutants in the Underground Water (A Case Study: Sarvestan Plain)

Abstract. The efficient and appropriate use of basic resources in agriculture and considerations of environmental requirements not only it helps in producing healthy crops but also lead to sustainable agriculture. Planning for optimal use of water and soil resources on one hand and on the other hand, moderate consumption of inputs in other agricultural areas is a fundamental and important principle. This study is done based on the data of physic-chemical parameters including pH, electrical conductivity, bicarbonate and sodium absorption ratio in 29 water wells of the area located in Sarvestan Plain from 2005 to 2011 analyzed by Excel and GIS (Surfer10 version) applications. As the last step, the results of data analysis, diagrams, and zoning and geological maps as well as land use and GIS were compared with FAO standards in regard to irrigation water quality so as to enable further review and inferences. According to the results of data analysis and their comparison with FAO standard, it is estimated that electrical conductivity in 75% of wells have very high degrees of restrictions, the sodium absorption ratio of 65% of wells were of high and very high restrictions, bicarbonate content and acidity of 28 water wells were respectively had low to moderate restrictions and normal range of irrigation water quality as codified in FAO standards. The maximum value of parameters of sodium absorption ratio and electrical conductivity in wells 7 and 9 were respectively (45/6 – 49/7) decisiemens/m and (46/5 – 70/5) milliequivalents/liter. Due to recent droughts, reduction of precipitations, increase in temperature and evaporation intensity along with usage of chemical agricultural fertilizers and the kind of formations surrounding the plain bed as well as locations of wells 7 and 9 in the evaporative area of salty Maharloo Lake, the diffusion phenomenon and migration of salty water of the Lake towards the plain and its influence on underground water of plain are seemingly the most important factors of increasing electrical conductivity and sodium absorption ratio. Therefore, planning for continuous monitoring of water resources seems essential.

Rescue of the disrupted enamel phenotype in Slc4a4‐null mice using explant organ culture maintained in a living host kidney capsule (1098.8)

Slc4a4 encodes the electrogenic sodium base transporter NBCe1 that is involved in transcellular base transport and pH regulation during amelogenesis. Patients with mutations in the SLC4A4 gene and NBCe1‐/‐ mice present with dysplastic enamel, amongst other pathologies. Loss of NBCe1 function leads to local abnormalities in enamel matrix pH regulation and also results in systemic acidemic blood pH due to defecting renal bicarbonate absorption. Whether local changes in enamel pH/base transport and/or a decrease in systemic pH are the cause of the abnormal enamel phenotype is currently unknown. In the present study we addressed this question by explanting fetal wild‐type and Slc4a4‐null mandibles into healthy host kidney capsules to study enamel formation in the absence of systemic acidemia. Mandibular E11.5 explants from NBCe1‐/‐ mice, maintained in host kidney capsules for 70 days, resulted in teeth with enamel and dentin with morphological and mineralization properties similar to cultured NBCe1+/+ mandibles grown under identical conditions. Despite the capacity of ameloblasts to dynamically modulate the local pH of the enamel matrix, at least in the NBCe1‐/‐ mice, the cause of the enamel phenotype appears primarily to be due to abnormalities in systemic pH. Extrapolating these data to humans, our findings suggest that in patients with NBCe1 mutations, correction of the systemic metabolic acidosis at a sufficiently early time point may lead to amelioration of enamel abnormalities.Grant Funding Source: NIH

Roles of renal proximal tubule transport in acid/base balance and blood pressure regulation.

Sodium-coupled bicarbonate absorption from renal proximal tubules (PTs) plays a pivotal role in the maintenance of systemic acid/base balance. Indeed, mutations in the Na+-HCO3 − cotransporter NBCe1, which mediates a majority of bicarbonate exit from PTs, cause severe proximal renal tubular acidosis associated with ocular and other extrarenal abnormalities. Sodium transport in PTs also plays an important role in the regulation of blood pressure. For example, PT transport stimulation by insulin may be involved in the pathogenesis of hypertension associated with insulin resistance. Type 1 angiotensin (Ang) II receptors in PT are critical for blood pressure homeostasis. Paradoxically, the effects of Ang II on PT transport are known to be biphasic. Unlike in other species, however, Ang II is recently shown to dose-dependently stimulate human PT transport via nitric oxide/cGMP/ERK pathway, which may represent a novel therapeutic target in human hypertension. In this paper, we will review the physiological and pathophysiological roles of PT transport.

Structure, function, and regulation of the SLC4 NBCe1 transporter and its role in causing proximal renal tubular acidosis

There has been significant progress in our understanding of the structural and functional properties and regulation of the electrogenic sodium bicarbonate cotansporter NBCe1, a membrane transporter that plays a key role in renal acid-base physiology. The NBCe1 variant NBCe1-A mediates basolateral electrogenic sodium-base transport in the proximal tubule and is critically required for transepithelial bicarbonate absorption. Mutations in NBCe1 cause autosomal recessive proximal renal tubular acidosis (pRTA). The review summarizes recent advances in this area. A topological model of NBCe1 has been established that provides a foundation for future structure-functional studies of the transporter. Critical residues and regions have been identified in NBCe1 that play key roles in its structure, function (substrate transport, electrogenicity) and regulation. The mechanisms of how NBCe1 mutations cause pRTA have also recently been elucidated. Given the important role of proximal tubule transepithelial bicarbonate absorption in systemic acid-base balance, a clear understanding of the structure-functional properties of NBCe1 is a prerequisite for elucidating the mechanisms of defective transepithelial bicarbonate transport in pRTA.

The calcium sensing receptor modulates fluid reabsorption and acid secretion in the proximal tubule

The proximal tubule uses a complex process of apical acid secretion and basolateral bicarbonate absorption to regulate both luminal acidification and fluid absorption. One of the primary regulators of apical acid secretion is the luminal sodium-hydrogen exchanger expressed along the apical membrane of the proximal tubule. Similarly, the calcium-sensing receptor (CaSR) is also located along the luminal membrane of the proximal tubule. Here we investigated the role of CaSR in proton secretion and fluid reabsorption in proximal tubules by modulating luminal calcium concentration, using both in vivo micropuncture in rats and in vitro perfused mouse proximal tubules. Using CaSR knockout mice and a calcimimetic agent, we found that increased proton secretion and fluid reabsorption were CaSR dependent. Activating CaSR by either raising the luminal calcium ion concentration or by the calcimimetic caused a concomitant increase in sodium-dependent proton extrusion and fluid reabsorption, whereas in proximal tubules isolated from CaSR knockout mice varying calcium ion concentration had no effect. Application of a calcimimetic in lower concentrations of calcium ion stimulated these processes in vitro and in vivo. Thus, in both rats and mice, increased luminal calcium concentration leads to enhanced fluid reabsorption in the proximal tubule, a process related to activation of CaSR.

Proximal tubule specific knockout of the Na+/H+ exchanger NHE3: effects on bicarbonate absorption and ammonium excretion

The existing NHE3 knockout mouse has significant intestinal electrolyte absorption defects, making this model unsuitable for the examination of the role of proximal tubule NHE3 in pathophysiologic states in vivo. To overcome this problem, we generated proximal convoluted tubule-specific KO mice (NHE3-PT KO) by generating and crossing NHE3 floxed mice with the sodium-glucose transporter 2 Cre transgenic mice. The NHE3-PT KO mice have >80 % ablation of NHE3 as determined by immunofluorescence microscopy, western blot, and northern analyses, and show mild metabolic acidosis (serum bicarbonate of 21.2 mEq/l in KO vs. 23.7 mEq/l in WT, p < 0.05). In vitro microperfusion studies in the isolated proximal convoluted tubules demonstrated a ∼36 % reduction in bicarbonate reabsorption (J HCO3 = 53.52 ± 4.61 pmol/min/mm in KO vs. 83.09 ± 9.73 in WT) and a ∼27 % reduction in volume reabsorption (J v = 0.67 ± 0.07 nl/min/mm in KO vs. 0.92 ± 0.06 nl/min/mm in WT) in mutant mice. The NHE3-PT KO mice tolerated NH4Cl acid load well (added to the drinking water) and showed NH4 excretion rates comparable to WT mice at 2 and 5 days after NH4Cl loading without disproportionate metabolic acidosis after 5 days of acid load. Our results suggest that the Na+/H+ exchanger NHE3 plays an important role in fluid and bicarbonate reabsorption in the proximal convoluted tubule but does not play an important role in NH4 excretion.

Ezrin Is Required for the Functional Regulation of the Epithelial Sodium Proton Exchanger, NHE3

The sodium hydrogen exchanger isoform 3 (NHE3) mediates absorption of sodium, bicarbonate and water from renal and intestinal lumina. This activity is fundamental to the maintenance of a physiological plasma pH and blood pressure. To perform this function NHE3 must be present in the apical membrane of renal tubular and intestinal epithelia. The molecular determinants of this localization have not been conclusively determined, although linkage to the apical actin cytoskeleton through ezrin has been proposed. We set out to evaluate this hypothesis. Functional studies of NHE3 activity were performed on ezrin knockdown mice (Vil2kd/kd) and NHE3 activity similar to wild-type animals detected. Interpretation of this finding was difficult as other ERM (ezrin/radixin/moesin) proteins were present. We therefore generated an epithelial cell culture model where ezrin was the only detectable ERM. After knockdown of ezrin expression with siRNA, radixin and moesin expression remained undetectable. Consistent with the animal ultrastructural data, cells lacking ezrin retained an epithelial phenotype but had shortened and thicker microvilli. NHE3 localization was identical to cells transfected with non-targeting siRNA. The attachment of NHE3 to the apical cytoskeleton was unaltered as assessed by fluorescent recovery after photobleaching (FRAP) and the solubility of NHE3 in Triton X-100. Baseline NHE3 activity was unaltered, however, cAMP-dependent inhibition of NHE3 was largely lost even though NHE3 was phosphorylated at serines 552 and 605. Thus, ezrin is not necessary for the apical localization, attachment to the cytoskeleton, baseline activity or cAMP induced phosphrylation of NHE3, but instead is required for cAMP mediated inhibition.

Molecular mechanisms of renal and extrarenal manifestations caused by inactivation of the electrogenic Na+-HCO3− cotransporter NBCe1

The electrogenic Na+-HCO3− cotransporter NBCe1 plays an essential role in bicarbonate absorption from renal proximal tubules, but also mediates the other biological processes in extrarenal tissues such as bicarbonate secretion from pancreatic ducts, maintenance of tissue homeostasis in eye, enamel maturation in teeth, or local pH regulation in synapses. Homozygous mutation in NBCe1 cause proximal renal tubular acidosis (pRTA) associated with extrarenal manifestations such as short stature, ocular abnormalities, enamel abnormalities, and migraine. Functional analyses of NBCe1 mutants using different expression systems suggest that at least a 50% reduction of the transport activity may be required to induce severe pRTA. In addition to functional impairments, some NBCe1 mutants show trafficking defects. Some of the pRTA-related NBCe1 mutants showing the cytoplasmic retention have been shown to exert a dominant negative effect through hetero-oligomer complexes with wild-type NBCe1 that may explain the occurrence of extrarenal manifestations in the heterozygous carries of NBCe1 mutations. Both NBCe1 knockout (KO) and W516X knockin (KI) mice showed very severe pRTA and reproduced most of the clinical manifestations observed in human pRTA patients. Functional analysis on isolated renal proximal tubules from W516X KI mice directly confirmed the indispensable role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we will focus on the molecular mechanisms underling the renal and extrarenal manifestations caused by NBCe1 inactivation.

Proximal renal tubular acidosis mediated by mutations in NBCe1-A: unraveling the transporter's structure-functional properties

NBCe1 belongs to the SLC4 family of base transporting membrane proteins that plays a significant role in renal, extrarenal, and systemic acid-base homeostasis. Recent progress has been made in characterizing the structure-function properties of NBCe1 (encoded by the SLC4A4 gene), and those factors that regulate its function. In the kidney, the NBCe1-A variant that is expressed on the basolateral membrane of proximal tubule is the key transporter responsible for overall transepithelial bicarbonate absorption in this nephron segment. NBCe1 mutations impair transepithelial bicarbonate absorption causing the syndrome of proximal renal tubular acidosis (pRTA). Studies of naturally occurring NBCe1 mutant proteins in heterologous expression systems have been very helpful in elucidation the structure-functional properties of the transporter. NBCe1 mutations are now known to cause pRTA by various mechanisms including the alteration of the transporter function (substrate ion interaction, electrogenicity), abnormal processing to the plasma membrane, and a perturbation in its structural properties. The elucidation of how NBCe1 mutations cause pRTA in addition to the recent studies which have provided further insight into the topology of the transporter have played an important role in uncovering its critically important structural-function properties.