Abstract: TH-PO1021
The A-Splice Variant of NBCe1 (NBCe1-A) Regulates Citrate Excretion and NaDC1 Expression
Session Information
- Acid Base: Basic
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Fluid, Electrolytes, and Acid-Base
- 701 Acid-Base: Basic
Authors
- Osis, Gunars, University of Florida , Gainesville, Florida, United States
- Webster, Kierstin L, University of Florida , Gainesville, Florida, United States
- Holmes, Heather L., Mayo Clinic College of Medicine, Rochester, Minnesota, United States
- Rossano, Adam Joseph, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
- Romero, Michael F., Mayo Clinic College of Medicine, Rochester, Minnesota, United States
- Verlander, Jill W., University of Florida , Gainesville, Florida, United States
- Weiner, I. David, University of Florida , Gainesville, Florida, United States
Background
Urinary citrate affects several critical kidney functions, including acid-base homeostasis and prevention of calcium nephrolithiasis. Proximal tubule (PT) NaDC1 is believed to be the major regulator of urinary citrate excretion. These studies examined the role of the A-splice variant of NBCe1 (NBCe1-A) in basal and acidosis-stimulated citrate excretion and NaDC1 expression.
Methods
We used recently developed NBCe1-A-specific deletion (KO) mice and their wild-type (WT) littermates. We performed exogenous acid-loading with dietary HCl loading for 7 days. We used quantitative immunohistochemistry (qIHC) to examine NaDC1 expression in proximal convoluted tubule in the cortical labyrinth (PCT), proximal straight tubule (PST) in the medullary ray (PST-MR) and PST in the outer medulla (PST-OM). Urinary citrate was measured using 1H-NMR.
Results
In WT mice under basal conditions, NaDC1 immunolabel intensity exhibited significant axial heterogeneity, PCT < PST-MR < PST-OM. Under basal conditions, NBCe1-A deletion induces spontaneous metabolic acidosis. Despite the acidosis, which in normal conditions decreases citrate excretion, citrate excretion was significantly greater in KO than WT mice (~3x-fold). Quantitative IHC showed NaDC1 expression was significantly less in KO than WT mice in all PT sites. Exogenous acid-loading decreased urinary citrate excretion >98% in both genotypes such that final urinary citrate did not differ significantly between WT and KO mice. Exogenous acid-loading increased NaDC1 expression in WT mice in the PCT and PST-MR, but not the PST-OM. In KO mice, in contrast, exogenous acid-loading did not alter PCT NaDC1 expression significantly, but did increase expression significantly in both PST-MR and PST-OM.
Conclusion
1) Under basal conditions NBCe1-A expression is critical to the normal regulation of citrate excretion and NaDC1 expression; 2) in WT mice, there is significant axial heterogeneity of both basal NaDC1 expression and its response to acid-loading; and, 3) during exogenous acid-loading alternative signaling pathways in NBCe1-A KO mice increase NaDC1 expression with a different axial pattern than in WT mice. We conclude that NBCe1-A is critical for citrate metabolism through its regulation of normal NaDC1 expression under basal conditions and in response to acid-loading.
Funding
- NIDDK Support