低葡萄糖敏感性 TRPC6 功能障碍会导致糖尿病中低血糖引起的认知障碍
Low‐glucose‐sensitive TRPC6 dysfunction drives hypoglycemia‐induced cognitive impairment in diabetes.
Keywords：TRPC6; cognition impairment; diabetes; recurrent moderate hypoglycemia.
关键词：TRPC6；认知障碍；糖尿病; 复发性中度低血糖
作者：He Chengkang, Gao Peng, Cui Yuanting, Li Qiang, Li Yingsha, Lu Zongshi, Ma Huan, Zhao Yu, Li Li, Sun Fang, Chen Xiaowei, Jia Hongbo, Liu Daoyan, Yang Gangyi, Zheng Hongting, Zhu Zhiming
出版期刊：《Clin Transl Med》（2020/10/14）
Abstract：
Recurrent moderate hypoglycemia (RH), a major adverse effect of hypoglycemic therapy in diabetic patients, is one of the main risk factors for cognitive impairment and dementia. Transient receptor potential canonical channel 6 (TRPC6) is a potential therapeutic target for Alzheimer's disease (AD) and its expression is highly regulated by glucose concentration.
To investigate whether RH regulates the expression of TRPC6 in brain and whether TRPC6 dysfunction can drive hypoglycemia‐associated cognitive impairment in diabetes, and reveal the underlying mechanism.
Histological staining, in vivo two‐photon Ca2+ imaging, and behavioral tests were used to measure neuronal death, brain network activity, and cognitive function in mice, respectively. High‐resolution respirometry and transmission electron microscope were used to assess mitochondrial structure and function. Intracellular calcium measurement and molecular biology techniques were conducted to uncover the underlying mechanism.
Here, we report that the expression of TRPC6 in hippocampus was specifically repressed by RH in streptozocin‐induced type 1 diabetic mice, but not in nondiabetic mice. TRPC6 knockout directly leads to neuron loss, neuronal activity, and cognitive function impairment under diabetic condition, the degree of which is similar to that of RH. Activation of TRPC6 with hyperforin substantially improved RH‐induced cognitive impairment. Mechanistically, TRPC6 inhibited mitochondrial fission in the hippocampus of diabetic mice undergoing RH episodes by activating adenosine 5‘‐monophosphate‐activated protein kinase, and TRPC6‐mediated cytosolic calcium influx was required for this process. Clinically, dysfunction of TRPC6 was closely associated with cognitive impairment in type 2 diabetic patients with RH.
Our results indicate that TRPC6 is a critical sensitive cation channel to hypoglycemia and is a promising target to prevent RH‐induced cognitive impairment by properly orchestrating the mitochondrial dynamics in diabetic patients.
文章摘要：
复发性中度低血糖(RH)是糖尿病患者降糖治疗的主要不良反应,是认知障碍和痴呆的主要危险因素之一。瞬时受体电位经典通道 6 (TRPC6) 是阿尔茨海默病 (AD) 的潜在治疗靶点，其表达受葡萄糖浓度的高度调节。
研究 RH 是否调节大脑中 TRPC6 的表达，以及 TRPC6 功能障碍是否会驱动糖尿病患者的低血糖相关认知障碍，并揭示其潜在机制。
组织学染色、体内双光子 Ca 2+成像和行为测试分别用于测量小鼠的神经元死亡、脑网络活动和认知功能。高分辨率呼吸测定法和透射电子显微镜用于评估线粒体结构和功能。进行细胞内钙测量和分子生物学技术以揭示潜在机制。
在这里，我们报告说，在链脲佐菌素诱导的 1 型糖尿病小鼠中，RH 特异性抑制了海马中 TRPC6 的表达，但在非糖尿病小鼠中则没有。TRPC6敲除直接导致糖尿病状态下的神经元丢失、神经元活动和认知功能障碍，其程度与RH相似。用 hyperforin 激活 TRPC6 可显着改善 RH 诱导的认知障碍。从机制上讲，TRPC6 通过激活腺苷 5'-一磷酸活化蛋白激酶来抑制经历 RH 发作的糖尿病小鼠海马中的线粒体裂变，并且该过程需要 TRPC6 介导的细胞溶质钙内流。临床上，TRPC6 功能障碍与 2 型糖尿病合并 RH 患者的认知障碍密切相关。
我们的结果表明，TRPC6 是低血糖的关键敏感阳离子通道，是通过适当协调糖尿病患者的线粒体动力学来预防 RH 诱导的认知障碍的有希望的靶点。
点击链接即可查看和下载文章：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568851/pdf/CTM2-10-e205.pdf
文章题目、关键词与摘要译文仅用于参考。
