期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 22, 期 1, 页码 59-72出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2009121267
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资金
- National Institutes of Health [POIDK38452]
- National Kidney Foundation
- Natural Sciences and Engineering Research Council of Canada
- NIDDK, National Institutes of Health [K08 DK-075940-01]
- Boston Area Diabetes and Endocrinology Research Center [DK57521]
- Center for the Study of Inflammatory Bowel Disease [DK43341]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R29DK043341, P30DK043351, K08DK075940, P01DK038452, P30DK057521] Funding Source: NIH RePORTER
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.
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