Renal phosphate wasting in the absence of adenylyl cyclase 6.
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.
Interactions of Proteins in Epithelial Transport Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark;
Robert A
RA
Fenton
Department of Medicine, University of California San Diego, La Jolla, California;
Fiona
F
Murray
Department of Basic Sciences, Bastyr University California, San Diego, California;
Jessica A
JA
Dominguez Rieg
Veterans Affairs San Diego Healthcare System, San Diego, California; and.
Tong
T
Tang
Department of Medicine, University of Colorado Denver, Aurora, Colorado.
Moshe
M
Levi
Department of Medicine, University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California; and trieg@ucsd.edu.
Timo
T
Rieg
D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006706:Homeostasis; D006961:Hyperparathyroidism / Q000235:genetics; D054559:Hyperphosphatemia / Q000235:genetics; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010281:Parathyroid Hormone / Q000378:metabolism; D010641:Phenotype; D010710:Phosphates / Q000737:chemistry* / Q000652:urine; D021381:Protein Transport; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism
C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010710:Phosphates; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6