Renal phosphate wasting in the absence of adenylyl cyclase 6

J Am Soc Nephrol. 2014 Dec;25(12):2822-34. doi: 10.1681/ASN.2013101102. Epub 2014 May 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenylyl Cyclases / genetics*
  • Adenylyl Cyclases / metabolism
  • Animals
  • Cyclic AMP / metabolism
  • Female
  • 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*
  • Phosphates / urine
  • Protein Transport
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / metabolism

Substances

  • 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