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Abstract: SA-PO353

Cellular Remodeling of Cardiomyocytes: An Unappreciated Phenotype of Congenital Proximal Renal Tubular Acidosis?

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms


  • Brady, Clayton, State University of New York at Buffalo, Buffalo, New York, United States
  • Pearson, Myles, Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, United States
  • Marshall, Aniko, SUNY Buffalo, Buffalo, New York, United States
  • Parker, Mark, State University of New York at Buffalo, Buffalo, New York, United States

Proximal renal tubular acidosis is caused by mutations in SLC4A4 which encodes the electrogenic Na+/2HCO3 cotransporter variants NBCe1-A (predominantly renal and a major contributor to maintenance of plasma [HCO3]) and NBCe1-B/C (predominantly non-renal and contributes to regulation of cardiomyocyte pH). Our laboratory has recently characterized a strain of Nbce1b/c-knockout (KO) mice that maintains Nbce1a in the kidney with widespread loss of Nbce1b/c elsewhere, allowing for the study of Nbce1 loss in non-renal organ systems in the setting of a normally maintained pH. To date no cardiac phenotype has been reported in pRTA patients (in fact Nbce1b/c blockade is considered to be cardioprotective under certain circumstances) yet studies of cardiomyocytes isolated from spontaneously-hypertensive rats, in which Nbce1b/c activity is also impaired, reveal compensatory upregulation of the electroneutral Na+/HCO3- co-transporter Nbcn1 and hypertrophy. Nbcn1 activity is predicted to impose a greater Na+ load than Nbce1 activity. This is hypothesized to affect the activity of the Na+-Ca2+ exchanger, decreasing Ca2+ extrusion, and ultimately activating Ca2+ dependent growth pathways. In the present study, we assess the hearts of Nbce1b/c-KO mice for signs of this pro-hypertrophic pathway.


Cardiac tissue from age and gender-matched C57 wild-type (WT) and KO littermates was weighed post-dissection and normalized to body weight for comparison. Cardiac tissue homogenates were prepared for RT-qPCR and western blot analysis of Nbcn1 expression.


KO mice had 22 ± 8% larger heart-to-body weight ratios (n=5, p=0.03). Abundance of NBCn1 transcripts was 45 ± 10% greater in the KO compared to the WT (n=3, p=0.02). Abundance of NBCn1 protein was 85 ± 17% greater in the KO compared to WT mice (n=3, p<0.05).


Nbcn1 is upregulated both at the level of transcript and protein within cardiomyocytes of the enlarged hearts of Nbce1b/c-KO mice, consistent with the hypothesis that remodeling of acid/base transporter expression contributes to the enhanced growth of cardiac tissue.