Abstract: SA-PO225
Phosphate Transport through the Type II Sodium Phosphate Cotransporter Npt2a Regulates Metabolism Independent of Phosphate Level
Session Information
- CKD-MBD: Basic and Translational
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Lederer, Eleanor D., The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
- Gagnon, Kenneth Bradley, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
- Gaweda, Adam E., University of Louisville School of Medicine, Louisville, Kentucky, United States
- Baniasadi, Hamid, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Background
Npt2a expression and function in proximal tubule (PT) are regulated by the Na-H Exchanger Regulatory Factor Isoform 1 (NHERF1). Absence of NHERF1 (NHERF1 KO) is associated with phosphaturia and a metabolic shift toward increased activity of the pentose phosphate pathway and altered glutathione levels. Whether the metabolic shift in NHERF1 KO cortex is due to phosphate (Pi) deficiency or decreased functional Npt2a expression is unknown. We postulate that the metabolic shift is a result of decreased Npt2a-mediated Pi transport.
Methods
To address our hypothesis, we compared the kidney cortex metabolic profile from WT C57/Bl6 mice with kidney cortex from three models of hypophosphatemia: NHERF1 KO, Npt2a KO, and WT on low Pi diet (0.02%) for 2 weeks. Kidney cortices were subjected to targeted metabolomic assay followed by identification and pathway analysis of significantly different metabolites by Sparse Autoencoder Enabled Neural Network or Metaboanalyst 6.0 (principal component analysis) and pathway analysis.
Results
All hypophosphatemic conditions resulted in altered kidney cortex metabolomics when compared to wild type. WT compared to NHERF1 KO showed significant differences in metabolites related to arginine and proline metabolism, pentose phosphate pathway, and pyrimidine metabolism. WT compared to Npt2a KO showed significant differences in metabolites related to TCA cycle, glucose and pyruvate metabolism, the pentose phosphate pathway, and lysine degradation. WT compared to low Pi diet showed significant differences in their metabolomic profiles, primarily involving amino acid metabolism. Comparison of the metabolomic profiles of NHERF1 KO and Npt2a KO showed significant though not complete overlap (PC 1 42.9%, PC 2 18.7%). In contrast, comparison of NHERF1 KO and low Pi diet kidney cortex showed complete dissociation in metabolic profile.
Conclusion
We conclude that the metabolic shift associated wtih NHERF1 KO deficiency is largely due to loss of Npt2a-mediated Pi transport and not due to Pi deficiency. We also conclude that additional NHERF1-mediated transport processes may contribute to the metabolic shift seen in NHERF1 KO.
Funding
- Veterans Affairs Support