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Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice.

ABSTRACT: Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 h forward by corticosterone administration at the inactive phase. Moreover, the bladder clock shifted 8-12 h in mice that underwent both bilateral adrenalectomy and corticosterone administration at the inactive phase. These mice showed decreases in the diurnal rhythm of volume voided per micturition, while maintaining diurnal activity rhythms. These results indicate that the diurnal rhythm of glucocorticoid signaling is a zeitgeber that overcomes other bladder clock entrainment factors and coordinates the diurnal rhythm of volume voided per micturition.

SUBMITTER: Chihara I

PROVIDER: S-EPMC9867708 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice.

Chihara Ichiro I Negoro Hiromitsu H Kono Jin J Nagumo Yoshiyuki Y Tsuchiya Haruki H Kojo Kosuke K Shiga Masanobu M Tanaka Ken K Kandori Shuya S Mathis Bryan J BJ Nishiyama Hiroyuki H

Communications biology 20230121 1

Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 h forwar ...[more]

PMID: 36681730

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Project description:The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (5'DFCR), 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5'DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, Cmax and AUC0-6h values of 5'DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5'DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.

Dataset Information

Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice.

Publications

Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice.

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