Kidney Week

Abstract: TH-OR88

Left Ventricular Systolic Dysfunction in the NBCe1-B/C Knockout Mouse: A Possible Unappreciated Phenotype of Congenital Proximal Renal Tubular Acidosis (pRTA)

Session Information

• Mechanisms of Hypertension and Cardiorenal Disease: From the Vasculature to the Gut
  November 02, 2023 | Location: Room 108, Pennsylvania Convention Center
  Abstract Time: 05:33 PM - 05:42 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Brady, Clayton, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, United States

Clayton Brady

• Marshall, Aniko, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, United States

Aniko Marshall,

• Eagler, Lisa A., University at Buffalo, Buffalo, New York, United States

Lisa A. Eagler,

• Pon, Thomas M., University at Buffalo, Buffalo, New York, United States

Thomas M. Pon,

• Weil, Brian R., University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, United States

Brian R. Weil,

• Lang, Jennifer K., University at Buffalo, Buffalo, New York, United States

Jennifer K. Lang,

• Parker, Mark, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, United States

Mark Parker,

Background

Congenital proximal renal tubular acidosis (pRTA) is caused by autosomal recessive mutations in the SLC4A4 gene that encodes the electrogenic Na⁺/2HCO₃⁻ cotransporter NBCe1. Congenital pRTA is characterized by severe acidemia due to the loss of the kidney-specific NBCe1-A variant, which consequently impairs proximal tubule HCO₃^- transport. However, congenital pRTA also presents with growth retardation, intellectual disability, and ocular and dental abnormalities. Intriguingly, a mouse model lacking NBCe1-B and NBCe1-C (variants which have predominantly extra-renal expression) but with intact NBCe1-A, recapitulates the spectrum of ailments of congenital pRTA without the acidemia. No cardiac phenotype has been reported in congenital pRTA patients, however recent evidence from a virally-induced partial knockdown of cardiac NBCe1 in rats suggests that NBCe1-B is cardioprotective. Therefore, we assessed NBCe1-B/C knockout mice (KO_b/c) for signs of cardiac impairment.

Methods

Echocardiography, intraventricular pressure-volume (PV), and electrocardiogram measurements were used to assess cardiac function in vivo. Heart-weight to body-weight ratio and cardiomyocyte area were used to assess for signs of cardiac hypertrophy. The Ca²⁺-sensitive dye Fura-2 AM and an IonOptix imaging system was used to assess Ca²⁺-transients in isolated cardiomyocytes. Lastly, RNA-seq was used to investigate transcriptional changes in KO_b/c hearts.

Results

We observed elevated end-diastolic and end-systolic volumes as well as a reduced left ventricular ejection fraction in KO_b/c mice. PV loop analysis revealed reductions in load-independent contractility but not relaxation. Cardiac hypertrophy was not present in KO_b/c mice. The QT interval was not different between genotypes, however we observed increased QT variability in KO_b/c mice. We further found a reduction in the amplitude of Ca²⁺-transients in cardiomyocytes isolated from KO_b/c mice, providing an explanation for the reduction in contractility. Lastly, RNA-seq analysis revealed upregulation of gene-sets associated with membrane excitability and calcium handling.

Conclusion

We conclude that congenital absence of cardiac NBCe1-B leads to mechanical and electrical cardiac dysfunction in KO_b/c mice that is likely driven by dysregulated cardiomyocyte Ca²⁺-handling.

Funding

• NIDDK Support