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Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice
- Source :
- J Am Soc Nephrol
- Publication Year :
- 2019
- Publisher :
- American Society of Nephrology, 2019.
-
Abstract
- Background The SLC4A4 gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in SLC4A4 causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning. Alkali therapy remains the preferred treatment for pRTA, but it is unclear which nonrenal signs are secondary to acidemia and which are a direct consequence of NBCe1 loss from nonrenal sites (such as the eye and enamel organ) and therefore require separate therapy. SLC4A4 encodes three major NBCe1 variants: NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A is expressed in proximal tubule epithelia; its dysfunction causes the plasma bicarbonate insufficiency that underlies acidemia. NBCe1-B and NBCe1-C exhibit a broad extra-proximal-tubular distribution. Methods To explore the consequences of Nbce1b/c loss in the absence of acidemia, we engineered a novel strain of Nbce1b/c-null mice and assessed them for signs of pRTA. Results Nbce1b/c-null mice have normal blood pH, but exhibit increased mortality, growth retardation, corneal edema, and tooth enamel defects. Conclusions The correction of pRTA-related acidemia should not be considered a panacea for all signs of pRTA. The phenotype of Nbce1b/c-null mice highlights the physiologic importance of NBCe1 variants expressed beyond the proximal tubular epithelia and potential limitations of pH correction by alkali therapy in pRTA. It also suggests a novel genetic locus for corneal dystrophy and enamel hypomineralization without acidemia.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Mutation, Missense
Corneal dystrophy
03 medical and health sciences
Mice
0302 clinical medicine
Internal medicine
Medicine
Animals
Mice, Knockout
Analysis of Variance
biology
business.industry
Sodium-Bicarbonate Symporters
Enamel organ
Chronic metabolic acidosis
Metabolic acidosis
General Medicine
Acidosis, Renal Tubular
Tooth enamel
medicine.disease
Bicarbonates
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Basic Research
Phenotype
Gene Expression Regulation
Nephrology
Failure to thrive
biology.protein
Acidosis, Respiratory
medicine.symptom
Blood Gas Analysis
business
SLC4A4
Acidosis
Proximal renal tubular acidosis
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- J Am Soc Nephrol
- Accession number :
- edsair.doi.dedup.....de1caa117cae859b9335520174b8244c