Calcitonin has a vasopressin-like effect on aquaporin-2 trafficking and urinary concentration.
The most common cause of hereditary nephrogenic diabetes insipidus is a nonfunctional vasopressin (VP) receptor type 2 (V2R). Calcitonin, another ligand of G-protein-coupled receptors, has a VP-like effect on electrolytes and water reabsorption, suggesting that it may affect AQP2 trafficking. Here, calcitonin increased intracellular cAMP and stimulated the membrane accumulation of AQP2 in LLC-PK1 cells. Pharmacologic inhibition of protein kinase A (PKA) and deficiency of a critical PKA phosphorylation site on AQP2 both prevented calcitonin-induced membrane accumulation of AQP2. Fluorescence assays showed that calcitonin led to a 70% increase in exocytosis and a 20% decrease in endocytosis of AQP2. Immunostaining of rat kidney slices demonstrated that calcitonin induced a significant redistribution of AQP2 to the apical membrane of principal cells in cortical collecting ducts and connecting segments but not in the inner stripe or inner medulla. Calcitonin-treated VP-deficient Brattleboro rats had a reduced urine flow and two-fold higher urine osmolality during the first 12 hours of treatment compared with control groups. Although this VP-like effect of calcitonin diminished over the following 72 hours, the tachyphylaxis was reversible. Taken together, these data show that calcitonin induces cAMP-dependent AQP2 trafficking in cortical collecting and connecting tubules in parallel with an increase in urine concentration. This suggests that calcitonin has a potential therapeutic use in nephrogenic diabetes insipidus.
Massachusetts General Hospital, Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Simches Research Center, Room 8202, 185 Cambridge Street, Boston, MA 02114, USA. Bouley.Richard@mgh.harvard.edu
Richard
R
Bouley
Hua A J
HA
Lu
Paula
P
Nunes
Nicolas
N
Da Silva
Margaret
M
McLaughlin
Ying
Y
Chen
Dennis
D
Brown
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism*; D002116:Calcitonin / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018374:LLC-PK1 Cells; D008297:Male; D023421:Models, Animal; D009994:Osmolar Concentration; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011910:Rats, Brattleboro; D013552:Swine; D014556:Urine / Q000502:physiology*; D014667:Vasopressins / Q000494:pharmacology
D051399:Aquaporin 2; D014667:Vasopressins; D002116:Calcitonin; D000242:Cyclic AMP