Abstract: TH-PO310
The Proximal Tubule Regulates Collecting Duct Phenotypic and Remodeling Responses to Acidosis
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders
- 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic
Authors
- Lee, Hyun-Wook, University of Florida College of Medicine, Gainesville, Florida, United States
- Verlander, Jill W., University of Florida College of Medicine, Gainesville, Florida, United States
- Wall, Susan M., Emory University, Atlanta, Georgia, United States
- Harris, Autumn N., University of Florida College of Veterinary Medicine, Gainesville, Florida, United States
- Weiner, I. David, University of Florida College of Medicine, Gainesville, Florida, United States
Background
The collecting duct responds to acidosis with several phenotypic and remodeling responses that increase net acid excretion. The current studies examine whether the proximal tubule (PT) regulates these collecting duct responses.
Methods
We examined mice with deletion of proteins present only in the PT, either the A variant or both A and B variants of the electrogenic Na-bicarbonate cotransporter, isoform 1 (NBCe1). These deletions disrupt PT bicarbonate, ammonia, and citrate responses to acidosis. We then quantified the collecting duct phenotypic responses to the spontaneous metabolic acidosis that was spontaneously present and the remodeling responses to exogenous acid loading. 2-oxoglutarate was measured using H-NMR.
Results
Both NBCe1-A KO and combined renal NBCe1-A/B KO caused severe metabolic acidosis. In NBCe1-A KO mice, despite this acidosis, Type-A intercalated cells in the inner stripe of the outer medulla (ISOM) exhibited decreased height and reduced H-ATPase, anion exchanger 1, Rhesus B glycoprotein, and Rhesus C glycoprotein expression. Similar findings were present in mice with combined kidney-specific NBCe1-A/B deletion. Pendrin expression in non-A, non-B intercalated cells and in Type B intercalated cells was not altered by NBCe1-A KO despite the associated acidosis. Ultrastructural analysis showed decreased apical plasma membrane and increased vesicular H-ATPase in the ISOM Type-A intercalated cell in NBCe1-A KO mice. The collecting duct remodeling response to acidosis was also disrupted by PT NBCe1 deletion. In WT mice, acid-loading increased the proportion of Type-A intercalated cells in the connecting tubule and the ISOM, and it decreased the proportion of non-A, non-B intercalated cells and Type-B intercalated cells in the CNT and cortical collecting duct, respectively. These changes were absent in NBCe1-A KO mice. Urinary 2-oxoglutarate, which can alter intercalated cell function, did not differ significantly between WT and KO mice, either under basal conditions or after acid-loading.
Conclusion
Collecting duct phenotypic characteristics and remodeling responses to acidosis depend on intact proximal tubule acid-base responsiveness in two different genetic models. We conclude that proximal tubule-dependent signaling mechanisms are a major determinant of the collecting duct responses to metabolic acidosis.
Funding
- NIDDK Support