Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis

Abstract

We have identified a novel homozygous nonsense mutation (W516X) in the kidney-type electrogenic sodium bicarbonate cotransporter 1 (NBC1) in a patient with isolated proximal renal tubular acidosis (pRTA). To specifically address the pathogenesis of this mutation, we created NBC1 W516X knock-in mice to match the patient's abnormalities. The expression of NBC1 mRNA and protein in the kidneys of NBC1(W516X/W516X) mice were virtually absent, indicating that nonsense-mediated mRNA decay (NMD) is involved in the defective transcription and translation of this mutation. These mice not only recapitulated the phenotypes of this patient with growth retardation, pRTA, and ocular abnormalities, but also showed anemia, volume depletion, prerenal azotemia, and several organ abnormalities, culminating in dehydration and renal failure with early lethality before weaning. In isolated renal proximal tubules, both NBC1 activity and the rate of bicarbonate absorption were markedly reduced. Unexpectedly, there was no compensatory increase in mRNA of distal acid/base transporters. Sodium bicarbonate but not saline administration to these mutant mice markedly prolonged their survival, decreased their protein catabolism and attenuated organ abnormalities. The prolonged survival time uncovered the development of corneal opacities due to corneal edema. Thus, NBC1(W516X/W516X) mice with pRTA represent an animal model for metabolic acidosis and may be useful for testing therapeutic inhibition of NMD in vivo.

Pathophysiological Roles of Mutations in the Electrogenic Na+-HCO - Cotransporter NBCe1

“…Consistent with this view, the homozygous inactivating mutations in NBCe1A cause severe pRTA with the blood bicarbonate concentration often less than 10 mM [3][4][5][6][7][8][9][10][11]. Functional deletion of NBCe1 in mice produces even more severe acidemia with the blood bicarbonate concentration around 5 mM [11,14].…”

“…Consistent with this view, the homozygous inactivating mutations in NBCe1A cause severe pRTA with the blood bicarbonate concentration often less than 10 mM [3][4][5][6][7][8][9][10][11]. Functional deletion of NBCe1 in mice produces even more severe acidemia with the blood bicarbonate concentration around 5 mM [11,14]. By contrast, functional deletion of Cl -/HCO3 -exchanger AE1, which is responsible for a majority of basolateral bicarbonate exit from α-intercalated duct cells, produces only moderate acidemia in mice with the blood bicarbonate concentration around 17 mM [37].…”

“…Two types of NBCe1-deficient mice, NBCe1 KO and W516X knockin (KI) mice, have been produced [11,14]. Both types of mice show severe acidosis and early lethality.…”

“…Consistent with an essential role of NBCe1 in bicarbonate absorption from renal proximal tubules, homozygous mutations in NBCe1 cause proximal renal tubular acidosis (pRTA) [3][4][5][6][7][8][9][10][11]. These pRTA patients with NBCe1 mutations invariably present with ocular abnormalities such as band keratopathy, cataract, and glaucoma, indicating that NBCe1 also plays important roles in the maintenance of ocular homeostasis [12,13].…”

“…Some pRTA patients also have migraine, suggesting that NBCe1 may also contribute to the pH regulation in the brain [10]. In addition, mice models for NBCe1 deficiency have been developed [11,14].…”