Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: Circulating REG3A (the human homologue of mouse Reg3g) in heart transplantation patients treated with tacrolimus was detected. The glucose-stimulated insulin secretion and mitochondrial functions, including mitochondria membrane potential ( MMP), mitochondria calcium, ATP production, oxygen consumption rate and mitochondrial morphology were investigated in β-cells. Additionally, effects of Reg3g on tacrolimus-induced NODM in mice were analysed. KEY RESULTS: Circulating REG3A level in heart transplantation patients with NODM significantly decreased compared with those without diabetes. Tacrolimus down-regulated Reg3g via inhibiting STAT3-mediated transcription activation. Moreover, Reg3g restored glucose-stimulated insulin secretion suppressed by tacrolimus in β-cells by improving mitochondrial functions, including increased MMP, mitochondria calcium uptake, ATP production, oxygen consumption rate and contributing to an intact mitochondrial morphology. Mechanistically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signalling pathway, leading to restoration of tacrolimus-induced mitochondrial impairment. Reg3g overexpression also effectively mitigated tacrolimus-induced NODM in mice. CONCLUSION AND IMPLICATIONS: Reg3g can significantly ameliorate tacrolimus-induced β-cell dysfunction by restoring mitochondrial function in a pSTAT3(Ser727)-dependent manner. Our observations identify a novel Reg3g-mediated mechanism that is involved in tacrolimus-induced NODM and establish the novel role of Reg3g in reversing tacrolimus-induced β-cell dysfunction.
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Authors | Senlin Li, Hong Zhou, Mengyuan Xie, Zijun Zhang, Jing Gou, Jian Yang, Cheng Tian, Kun Ma, Cong-Yi Wang, Yi Lu, Qing Li, Wen Peng, Ming Xiang |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 179
Issue 12
Pg. 3078-3095
(06 2022)
ISSN: 1476-5381 [Electronic] England |
PMID | 35060126
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2022 The British Pharmacological Society. |
Chemical References |
- Adenosine Triphosphate
- Calcium
- Glucose
- Insulin
- Pancreatitis-Associated Proteins
- Proteins
- Reg3g protein, mouse
- Tacrolimus
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Topics |
- Animals
- Humans
- Mice
- Adenosine Triphosphate
(metabolism)
- Calcium
(metabolism)
- Glucose
(metabolism)
- Insulin
(metabolism)
- Insulin-Secreting Cells
(metabolism)
- Mitochondria
(metabolism)
- Pancreatitis-Associated Proteins
(metabolism, pharmacology)
- Proteins
(metabolism)
- Regeneration
- Tacrolimus
(adverse effects, metabolism)
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