Zhang C M, Huang X, Lu H L, Meng X M, Liu D H, Kim Young-Chul, Xu W X
Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China.
Department of Physiology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, 361-763, Republic of Korea.
Mol Cell Endocrinol. 2016 Mar 5;423:77-86. doi: 10.1016/j.mce.2016.01.002. Epub 2016 Jan 8.
The classic renin-angiotensin system (RAS) is a complex system in which angiotensin II (Ang II) has been identified as an important endogenous regulator that influences both smooth muscle contraction and cell growth. Although a local RAS is known to exist in the gastrointestinal tract, it is unclear whether Ang II is involved in the loss of gastric interstitial cells of Cajal (ICC) in diabetic mice. The present study was designed to investigate the effect of Ang II on ICC survival in streptozotocin (STZ)-induced diabetic mice. Western blot, immunofluorescence, isometric muscle recording, enzyme-linked immunosorbent assay (ELISA) and a cell counting kit-8 were used in this research. Our results demonstrate that the c-Kit and membrane-bound stem cell factor (mSCF) protein expression levels in gastric smooth muscle were decreased in STZ-induced diabetic mice. However, the angiotensin receptor type 1 (AT1R) expression levels in gastric smooth muscle and angiotensin-converting enzyme (ACE) expression levels in gastric mucosa were increased. The effect of Ang II on the tonic contraction of gastric smooth muscle was potentiated in diabetic mice, and the plasma Ang II level was enhanced. Ang II increased mSCF expression, cell proliferation, and Akt-Ser473 phosphorylation in cultured gastric smooth muscle cells (GSMCs). These effects were reduced by specific inhibitors ZD7155 (an AT1R antagonist) and LY294002 (a PI3-kinase inhibitor). Our results suggest that Ang II increases mSCF expression and cell proliferation in cultured GSMCs in a PI3K/Akt signaling-dependent manner. ACE and AT1R up-regulation in the stomach may help compensate for ICC loss in STZ-induced diabetic mice.
经典肾素-血管紧张素系统（RAS）是一个复杂的系统，其中血管紧张素II（Ang II）已被确定为一种重要的内源性调节因子，它影响平滑肌收缩和细胞生长。尽管已知胃肠道中存在局部RAS，但尚不清楚Ang II是否参与糖尿病小鼠胃Cajal间质细胞（ICC）的丢失。本研究旨在探讨Ang II对链脲佐菌素（STZ）诱导的糖尿病小鼠ICC存活的影响。本研究采用蛋白质免疫印迹法、免疫荧光法、等长肌肉记录法、酶联免疫吸附测定（ELISA）法和细胞计数试剂盒-8。我们的结果表明，STZ诱导的糖尿病小鼠胃平滑肌中c-Kit和膜结合干细胞因子（mSCF）蛋白表达水平降低。然而，胃平滑肌中血管紧张素1型受体（AT1R）表达水平和胃黏膜中血管紧张素转换酶（ACE）表达水平升高。Ang II对糖尿病小鼠胃平滑肌紧张性收缩的作用增强，血浆Ang II水平升高。Ang II增加了培养的胃平滑肌细胞（GSMCs）中mSCF的表达、细胞增殖和Akt-Ser473磷酸化。特异性抑制剂ZD7155（一种AT1R拮抗剂）和LY294002（一种PI3激酶抑制剂）可降低这些作用。我们的结果表明，Ang II以PI3K/Akt信号依赖的方式增加培养的GSMCs中mSCF的表达和细胞增殖。胃中ACE和AT1R的上调可能有助于补偿STZ诱导的糖尿病小鼠中的ICC丢失。
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