Search Results (2)

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KO_b/c) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KO_b/c mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure–volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KO_b/c mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca²⁺ transients in paced KO_b/c cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KO_b/c mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues. Full article

Acid-base homeostasis is crucial for numerous physiological processes. ${\mathrm{Na}}^{+}/{\mathrm{HCO}}_3^{-}$ cotransporters (NBCs) belong to the solute carrier 4 (SLC4) family, which regulates intracellular pH as well as ${\mathrm{HCO}}_3^{-}$ absorption and secretion. However, knowledge of the structural functions of these proteins remains limited. Electrogenic NBC (NBCe-1) is thought to be the primary factor promoting the precise acid–base equilibrium in distinct cell types for filtration and reabsorption, as well as the function of neurons and glia. NBC dysregulation is strongly linked to several diseases. As such, the need for special drugs that interfere with the transmission function of NBC is becoming increasingly urgent. In this review, we focus on the structural and functional characteristics of NBCe1, and discuss the roles of NBCe1 in the kidney, central nervous system (CNS), and related disorders, we also summarize the research on NBC inhibitors. NBCe1 and the related pathways should be further investigated, so that new medications may be developed to address the related conditions. Full article