Deficient acid handling with distal RTA in the NBCe2 knockout mouse

Wen, Duo; Yuan, Ye; Cornelius, Ryan J.; Li, Huaqing; Warner, Paige; Wang, Bangchen; Wang-France, Jun; Boettger, Thomas; Sansom, Steven C.

doi:10.1152/ajprenal.00163.2015

Cited by 10 publications

(9 citation statements)

References 45 publications

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“…Because ~20% of patients with dRTA do not have mutations in genes for H + -ATPase or AE1, additional candidate genes have been identified in mouse models of dRTA 3,6. These include HK α 2 (colonic H + –K + -ATPase),75 Kcc4 (K + –Cl − co-transporter, Kcc4),76 genes for the H + -ATPase C, G, and d subunits,77 Foxi1 (the Forkhead transcription factor, Foxi1),78 Rhcg (the ammonia transporter, Rhcg),79,80 Slc26a7 (Cl − –HCO3 − exchanger, Slc26a7, co-localized with AE1),81 DMBT1 (component of the pathway of acidosis-induced conversion of B-ICs into A-ICs, hensin),11 GPR4 (proton sensing G protein-coupled receptor, GPR4),82 NHE4 (Na + –H + exchanger 4, NHE4),83 SLC4A5 (Na + –HCO3 − co-transporter, NBCe2),84 Atp6ap2 (ATPase H + transporting lysosomal accessory protein 2, atp6ap2),85 and Ncoa7 (nuclear receptor coactivator 7, Ncoa7: an H + -ATPase interacting protein), as shown in Table 2 86. Although most of these genes have not been previously identified in human disease, Enerbäck et al identified homozygous FOXI1 mutations in two families with AR dRTA and early-onset SNHL 87.…”

Section: Ar Ae1 Gene (Slc4a1) Mutationsmentioning

confidence: 99%

Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead

Watanabe¹

2018

PHMT

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Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal acidification due to a failure of type A intercalated cells (A-ICs) in the collecting tubule. dRTA is characterized by persistent hyperchloremia, a normal plasma anion gap, and the inability to maximally lower urinary pH in the presence of systemic metabolic acidosis. Common clinical features of dRTA include vomiting, failure to thrive, polyuria, hypercalciuria, hypocitraturia, nephrocalcinosis, nephrolithiasis, growth delay, and rickets. Mutations in genes encoding three distinct transport proteins in A-ICs have been identified as causes of dRTA, including the B1/ATP6V1B1 and a4/ATP6V0A4 subunits of the vacuolar-type H+-ATPase (H+-ATPase) and the chloride–bicarbonate exchanger AE1/SLC4A1. Homozygous or compound heterozygous mutations in ATP6V1B1 and ATP6V0A4 lead to autosomal recessive (AR) dRTA. dRTA caused by SLC4A1 mutations can occur with either autosomal dominant or AR transmission. Red blood cell abnormalities have been associated with AR dRTA due to SLC4A1 mutations, including hereditary spherocytosis, Southeast Asia ovalocytosis, and others. Some patients with dRTA exhibit atypical clinical features, including transient and reversible proximal tubular dysfunction and hyperammonemia. Incomplete dRTA presents with inadequate urinary acidification, but without spontaneous metabolic acidosis and recurrent urinary stones. Heterozygous mutations in the AE1 or H+-ATPase genes have recently been reported in patients with incomplete dRTA. Early and sufficient doses of alkali treatment are needed for patients with dRTA. Normalized serum bicarbonate, urinary calcium excretion, urinary low-molecular-weight protein levels, and growth rate are good markers of adherence to and/or efficacy of treatment. The prognosis of dRTA is generally good in patients with appropriate treatment. However, recent studies showed an increased frequency of chronic kidney disease (CKD) in patients with dRTA during long-term follow-up. The precise pathogenic mechanisms of CKD in patients with dRTA are unknown.

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Section: Ar Ae1 Gene (Slc4a1) Mutationsmentioning

confidence: 99%

Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead

Watanabe¹

2018

PHMT

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“…In mouse, in situ hybridization studies showed that NBCe2 co-localizes with AQP2, which indicates expression in the principal cells of the CD (Groger et al, 2012). NBCe2 was also detected in micro-isolated connecting tubules (CNT; Wen et al, 2015a), again without reporting how the purity of the samples was tested. Finally, a transcriptome study evaluating renal CD cells revealed that Slc4a5 expression was detected only in a few of the αand β-intercalated cell (2/87 and 1/23, respectively) as well as principal cell (2/74) samples (Chen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

NBCe2 (Slc4a5) Is Expressed in the Renal Connecting Tubules and Cortical Collecting Ducts and Mediates Base Extrusion

et al. 2020

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Arterial hypertension, is a common disorder with multiple and variable etiologies. Single nucleotide polymorphism analyses have detected an association between variants in the gene encoding the electrogenic Na + :HCO 3 − cotransporter NBCe2 (Slc4a5), and salt-sensitive hypertension. Mice with genetic deletion of NBCe2 are hypertensive, and the cause of the blood pressure (BP) increase is believed to arise from a lack of renal NBCe2 function. The exact cellular expression of NBCe2 in the kidney tubular system is, however, not determined. Here, we find NBCe2 to be expressed predominantly in isolated connecting tubules (CNT) and cortical collecting ducts (CD) by RT-PCR. In isolated renal CNT and CCD, genetic deletion of NBCe2 leads to decreased net base extrusion. To determine the role of renal NBCe2 in the development of hypertension, we generated CNT and intercalated cell NBCe2 knockout mice by crossing an Slc4a5 lox mouse with mice expressing cre recombinase under the V-ATPase B1 subunit promotor. Although the mice displayed changes in the expression of renal membrane transporters, we did not detect hypertension in these mice by tail cuff recordings. In conclusion, while global NBCe2 deletion certainly causes hypertension this study cannot confirm the role of renal NBCe2 expression in blood pressure regulation.

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“…Several additional mouse models of impaired type A IC H + secretion have been reported which are not yet known to be involved in human disease. These include mice with loss of KCC4 ( Slc12a7 ) (149), slc26a7 (90), Hensin (DMBT1)-CXCL12 complex (150), GPR4 (151,152), NBCe2 (153,154) and ATP6ap2 (155). Species differences also exist in that mice are not necessarily exact phenocopy models of human disease.…”

Section: Introductionmentioning

confidence: 99%

Renal Tubular Acidosis: H+/Base and Ammonia Transport Abnormalities and Clinical Syndromes

Kurtz¹

2018

Advances in Chronic Kidney Disease

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Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal HCO absorption or new renal HCO generation; (3) changes in renal NH, Ca, K, and HO homeostasis; and (4) extrarenal manifestations that provide etiologic diagnostic clues. The focus of this review is to give a general overview of the pathogenesis of the various clinical syndromes causing RTA with a particular emphasis on type I (hypokalemic distal RTA) and type II (proximal) RTA while reviewing their pathogenesis from a physiological "bottom-up" approach. In addition, the factors involved in the generation of metabolic acidosis in both type I and II RTA are reviewed highlighting the importance of altered renal ammonia production/partitioning and new HCO generation. Our understanding of the underlying tubular transport and extrarenal abnormalities has significantly improved since the first recognition of RTA as a clinical entity because of significant advances in clinical acid-base chemistry, whole tubule and single-cell H/base transport, and the molecular characterization of the various transporters and channels that are functionally affected in patients with RTA. Despite these advances, additional studies are needed to address the underlying mechanisms involved in hypokalemia, altered ammonia production/partitioning, hypercalciuria, nephrocalcinosis, cystic abnormalities, and CKD progression in these patients.

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Deficient acid handling with distal RTA in the NBCe2 knockout mouse

Cited by 10 publications

References 45 publications

Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead

Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead

NBCe2 (Slc4a5) Is Expressed in the Renal Connecting Tubules and Cortical Collecting Ducts and Mediates Base Extrusion

Renal Tubular Acidosis: H+/Base and Ammonia Transport Abnormalities and Clinical Syndromes

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