Renal phosphate wasting in the absence of adenylyl cyclase 6

Robert A Fenton, Fiona Murray, Jessica A Dominguez Rieg, Tong Tang, Moshe Levi, Timo Rieg

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2822-2834
Number of pages13
JournalJournal of the American Society of Nephrology
Issue number12
Early online date22 May 2014
Publication statusPublished - Dec 2014

Bibliographical note

We thank N. Aroonsakool, E.-M. Locke, I.-M. Paulsen, and M. Sharik
for technical assistance.
Development of the AC62/2 mice was supported by National Institutes
of HealthGrants P01HL6694 and HL088426 and Veterans Affairs
Grant 1101BX001515. This work was supported, in part, by National
Institutes of Health Grant R01DK066029 (to M.L.), O’Brien Center for
Acute Kidney Injury Research Grant P30DK079337 (to T.R.), American
Heart Association Grant 10SDG2610034 (to T.R.), American Society
of Nephrology Carl W. Gottschalk Research Scholar Grant (to T.R.),
Satellite Healthcare, a not-for-profit renal care provider (to T.R.), the
Lundbeck Foundation, the Danish Medical Research Council, the Novo
Nordisk Foundation (R.A.F.), and the Department of Veterans Affairs


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