Renal phosphate wasting in the absence of adenylyl cyclase 6.

Abstract

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) enhance phosphate excretion by the proximal tubule of the kidney by retrieval of the sodium-dependent phosphate transporters (Npt2a and Npt2c) from the apical plasma membrane. PTH activates adenylyl cyclase (AC) through PTH 1 receptors and stimulates the cAMP/PKA signaling pathway. However, the precise role and isoform(s) of AC in phosphate homeostasis are not known. We report here that mice lacking AC6 (AC6(-/-)) have increased plasma PTH and FGF-23 levels compared with wild-type (WT) mice but comparable plasma phosphate concentrations. Acute activation of the calcium-sensing receptor or feeding a zero phosphate diet almost completely suppressed plasma PTH levels in both AC6(-/-) and WT mice, indicating a secondary cause for hyperparathyroidism. Pharmacologic blockade of FGF receptors resulted in a comparable increase in plasma phosphate between genotypes, whereas urinary phosphate remained significantly higher in AC6(-/-) mice. Compared with WT mice, AC6(-/-) mice had reduced renal Npt2a and Npt2c protein abundance, with approximately 80% of Npt2a residing in lysosomes. WT mice responded to exogenous PTH with redistribution of Npt2a from proximal tubule microvilli to intracellular compartments and lysosomes alongside a PTH-induced dose-response relationship for fractional phosphate excretion and urinary cAMP excretion. These responses were absent in AC6(-/-) mice. In conclusion, AC6 in the proximal tubule modulates cAMP formation, Npt2a trafficking, and urinary phosphate excretion, which are highlighted by renal phosphate wasting in AC6(-/-) mice.

• Authors: Robert A Fenton, Fiona Murray, Jessica A Dominguez Rieg, Tong Tang, Moshe Levi, Timo Rieg
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 25 Issue 12 Pg. 2822-34 (Dec 2014) ISSN: 1533-3450 [Electronic] United States
• PMID: 24854272 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 by the American Society of Nephrology.

Chemical References

• Fgf23 protein, mouse
• Parathyroid Hormone
• Phosphates
• Slc34a1 protein, mouse
• Sodium-Phosphate Cotransporter Proteins, Type IIa
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• Cyclic AMP
• Adenylyl Cyclases
• adenylyl cyclase 6

Topics

• Adenylyl Cyclases (genetics, metabolism)
• Animals
• Cyclic AMP (metabolism)
• Female
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (metabolism)
• Homeostasis
• Hyperparathyroidism (genetics)
• Hyperphosphatemia (genetics)
• Immunohistochemistry
• Kidney (metabolism)
• Kidney Diseases (genetics)
• Lysosomes (metabolism)
• Male
• Mice
• Mice, Transgenic
• Parathyroid Hormone (metabolism)
• Phenotype
• Phosphates (chemistry, urine)
• Protein Transport
• Sodium-Phosphate Cotransporter Proteins, Type IIa (metabolism)