Dai Fang, Guo Jizheng, Wang Yang, Jiang Tian, Chen Hongbo, Hu Ying, Du Juan, Xia Xianming, Zhang Qiu, Shen Bing
Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
School of Basic Medicine, Anhui Medical University, Hefei, China.
Front Physiol. 2021 Oct 20;12:691867. doi: 10.3389/fphys.2021.691867. eCollection 2021.
The underlying mechanism of diabetic enteropathy, a common complication of type 1 diabetes, remains unclear. Store-operated Ca entry (SOCE) is a ubiquitous type of Ca influx involved in various cellular functions. Here, we show that SOCE-related stromal interaction molecule 1 (STIM1) and Orai1 participate in inappropriate cellular Ca homeostasis, augmenting agonist-induced small intestinal smooth muscle contraction and small bowel transit speed in a mouse model of type 1 diabetes. We used small interfering (si)RNA to suppress STIM1 and Orai1 proteins, and employed intracellular Ca, small intestinal contraction and intestinal transit speed measurement to investigate the functional change. We found that SOCE activity and Orai1 and STIM1 expression levels of small intestinal smooth muscle were significantly increased in cells cultured in high glucose medium or in diabetic mice. Gastrointestinal transit speed and SOCE-mediated contractions were markedly increased in diabetic mice; Knocking down Orai1 or STIM1 with siRNA rescued both alterations in diabetic mice. However, the Orai1-large conductance Ca-activated K (BK) channel interaction was decreased in diabetic mice, and suppressing Orai1 expression or inhibiting the BK channel increased agonist-induced small intestinal contractions in normal mice. We concluded that the increased SOCE caused by excessive STIM1 and Orai1 expression and decreased Orai1-BK interaction augmented small intestinal smooth muscle contraction and accelerated small bowel transit speed in diabetic mice. This finding demonstrates a pathological role for SOCE in diabetic enteropathy and provides a potential therapeutic target for diabetic enteropathy.
1型糖尿病常见并发症糖尿病性肠病的潜在机制尚不清楚。钙库操纵性钙内流（SOCE）是一种普遍存在的钙内流类型，参与多种细胞功能。在此，我们表明，与SOCE相关的基质相互作用分子1（STIM1）和Orai1参与了不适当的细胞钙稳态，在1型糖尿病小鼠模型中增强了激动剂诱导的小肠平滑肌收缩和小肠传输速度。我们使用小干扰（si）RNA抑制STIM1和Orai1蛋白，并采用细胞内钙、小肠收缩和肠道传输速度测量来研究功能变化。我们发现，在高糖培养基中培养的细胞或糖尿病小鼠中，小肠平滑肌的SOCE活性以及Orai1和STIM1表达水平显著增加。糖尿病小鼠的胃肠道传输速度和SOCE介导的收缩明显增加；用siRNA敲低Orai1或STIM1可挽救糖尿病小鼠的这两种改变。然而，糖尿病小鼠中Orai1与大电导钙激活钾（BK）通道的相互作用降低，抑制Orai1表达或抑制BK通道可增加正常小鼠中激动剂诱导的小肠收缩。我们得出结论，STIM1和Orai1表达过多导致SOCE增加以及Orai1-BK相互作用降低，增强了糖尿病小鼠小肠平滑肌收缩并加速了小肠传输速度。这一发现证明了SOCE在糖尿病性肠病中的病理作用，并为糖尿病性肠病提供了一个潜在的治疗靶点。
