Dataset Information

TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.

ABSTRACT: Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes in mice undergoing two surgical β-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for β-cell proliferation, increased β-cell workload and local inflammation, respectively. Our data suggest that TGFβ receptor signaling is necessary for baseline β-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased β-cell workload are both stimulants for β-cell proliferation but are TGFβ receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGFβ receptor-deleted mouse model, we have identified two distinct pathways that regulate adult β-cell proliferation. Our study thus provides important information for understanding β-cell proliferation during normal growth and in pancreatic diseases.

SUBMITTER: Xiao X

PROVIDER: S-EPMC3609557 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.

Xiao Xiangwei X Wiersch John J El-Gohary Yousef Y Guo Ping P Prasadan Krishna K Paredes Jose J Welsh Carey C Shiota Chiyo C Gittes George K GK

Diabetes 20121217 4

Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes ...[more]

PMID: 23248173

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Project description:The sympathetic system is involved in the arterial diseases, but its mechanism remains poorly understood. The present study aimed to explore the impact of the sympathetic neurotransmitter norepinephrine (NE) on transforming growth factor (TGF) β signaling and the role of NE in aortic remodeling. Guanethidine was used to induce a regional chemical sympathetic denervation (CSD) in angiotensin II (AngII) and β‑aminopropionitrile (BAPN)‑induced aortic aneurysm models. The diameter of the aorta was measured, and elastic fiber staining was performed. TGFβ type I receptor kinase (ALK5) expression in rat aortic NE‑treated vascular smooth muscle cells (VSMCs) was detected by reverse transcription‑quantitative PCR and western blotting. The effects of NE and ALK5 overexpression on migration, proliferation, apoptosis and TGFβ signaling were also evaluated. Furthermore, adrenergic receptor blockers were used to determine which receptor was involved in the modulation on TGFβ signaling by NE. The results of the present study demonstrated that CSD protected rats from AngII+BAPN‑induced aortic remodeling and aneurysm formation. Compared with the control group, NE inhibited VSMC proliferation and migration, but promoted apoptosis by suppressing ALK5 expression, reversing the effects of TGFβ signaling through the suppression of the SMAD‑dependent canonical pathway and promotion of the non‑canonical pathway. These effects were prevented by ALK5 overexpression. The inhibition of α‑ or β‑adrenergic receptors alleviated the NE‑mediated suppression of ALK5 expression. In conclusion, regional CSD protected rats from aortic aneurysm. NE inhibited SMAD2/3‑dependent TGFβ signaling by suppressing ALK5 expression, which may serve an important role in VSMC biological functions. Both α‑ and β‑adrenergic receptors were involved in the regulation of ALK5 expression by NE. Abnormal sympathetic innervation of the aorta may be used as a therapeutic target in aortic diseases.

Dataset Information

TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.

Publications

TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.

Similar Datasets

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