| RRC ID |
66131
|
| Author |
Sugimoto R, Watanabe H, Ikegami K, Enoki Y, Imafuku T, Sakaguchi Y, Murata M, Nishida K, Miyamura S, Ishima Y, Tanaka M, Matsushita K, Komaba H, Fukagawa M, Otagiri M, Maruyama T.
|
| Title |
Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism.
|
| Journal |
Kidney Int
|
| Abstract |
Hyperuricemia occurs with increasing frequency among patients with hyperparathyroidism. However, the molecular mechanism by which the serum parathyroid hormone (PTH) affects serum urate levels remains unknown. This was studied in uremic rats with secondary hyperparathyroidism where serum urate levels were found to be increased and urate excretion in the intestine and kidney decreased, presumably due to down-regulation of the expression of the urate exporter ABCG2 in intestinal and renal epithelial membranes. These effects were prevented by administration of the calcimimetic cinacalcet, a PTH suppressor, suggesting that PTH may down-regulate ABCG2 expression. This was directly tested in intestinal Caco-2 cells where the expression of ABCG2 on the plasma membrane was down-regulated by PTH (1-34) while its mRNA level remained unchanged. Interestingly, an inactive PTH derivative (13-34) had no effect, suggesting that a posttranscriptional regulatory system acts through the PTH receptor to regulate ABCG2 plasma membrane expression. As found in an animal study, additional clinical investigations showed that treatment with cinacalcet resulted in significant reductions in serum urate levels together with decreases in PTH levels in patients with secondary hyperparathyroidism undergoing dialysis. Thus, PTH down-regulates ABCG2 expression on the plasma membrane to suppress intestinal and renal urate excretion, and the effects of PTH can be prevented by cinacalcet treatment.
|
| Volume |
91(3)
|
| Pages |
658-670
|
| Published |
2017-3-1
|
| DOI |
10.1016/j.kint.2016.09.041
|
| PII |
S0085-2538(16)30597-X
|
| PMID |
27988213
|
| MeSH |
ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism*
Animals
Caco-2 Cells
Calcimimetic Agents / therapeutic use
Cinacalcet / therapeutic use
Disease Models, Animal
Down-Regulation
Humans
Hyperparathyroidism, Secondary / blood*
Hyperparathyroidism, Secondary / drug therapy
Hyperparathyroidism, Secondary / etiology
Hyperuricemia / blood
Hyperuricemia / etiology
Hyperuricemia / metabolism*
Hyperuricemia / prevention & control
Intestinal Elimination
Intestinal Mucosa / metabolism*
Intestines / drug effects
Kidney / drug effects
Kidney / metabolism*
Male
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Parathyroid Hormone / blood*
Parathyroid Hormone / pharmacology
Rats, Sprague-Dawley
Renal Elimination
Time Factors
Uremia / blood
Uremia / complications
Uric Acid / blood*
|
| IF |
8.945
|
| Resource |
| Human and Animal Cells |
CACO-2(RCB0988) |
