Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways.
Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways.
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糖耐量受损阶段的病理性高胰岛素血症和高血糖通过 miR-21、PTEN/AKT/eNOS 和 MARK/ET-1 通路介导内皮功能障碍
DOI：
10.3389/fendo.2021.644159
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发表时间：
2021
影响因子：
5.2
通讯作者：
Chang B
中科院分区：
文献类型：
--
作者：
Liu R;Guan S;Gao Z;Wang J;Xu J;Hao Z;Zhang Y;Yang S;Guo Z;Yang J;Shao H;Chang B
背景糖耐量受损（IGT）是糖尿病前期的一个重要阶段，其特征是血液中葡萄糖和胰岛素浓度升高。IGT时病理性高血糖和高胰岛素血症可能通过调节microRNA-21（miR-21）的表达，影响下游胰岛素信号通路，导致内皮细胞功能障碍和早期肾损害。方法采用人肾小球内皮细胞（HGECs）研究胰岛素和葡萄糖的单独及联合作用。检测细胞中miR-21、PTEN/AKT/eNOS和MAPK/ET-1通路蛋白的表达水平。同时测定细胞分泌的一氧化氮（NO）和内皮素-1（ET-1）水平。通过使用模拟物/抑制剂过表达/抑制该miRNA来评估miR-21在介导胰岛素和葡萄糖的调节作用中的作用。结果高浓度葡萄糖（>16.7 mmol/L）可上调miR-21的表达，激活和抑制PTEN/AKT/eNOS和MAPK/ET-1通路，上调NO的分泌，下调ET-1的分泌。高（>25 ng/mL）浓度的胰岛素下调miR-21的表达，并导致MAPK/ET-1的激活和PTEN/AKT/eNOS通路的抑制，从而上调ET-1的表达，下调NO. MiR-1的分泌，观察到当细胞用不同浓度的胰岛素共处理时，21通过直接控制胰岛素信号传导途径的活化而发挥关键作用。胰岛素和葡萄糖的浓度。发现miR-21的表达依赖于胰岛素和葡萄糖的相对浓度。在模拟IGT阶段的条件下（8.3 mmol/L葡萄糖+50 ng/mL胰岛素），高浓度胰岛素对细胞中miR-21表达的抑制作用减弱了高糖对miR-21表达的激活，导致miR-21表达下调，ET-1表达上调，NO分泌下调。结论高胰岛素和高葡萄糖浓度通过调节miRNA-21的表达，以相反的方式调节肾小球内皮细胞的分泌功能。IGT阶段胰岛素和葡萄糖的病理浓度可能导致miR-21表达减少，从而扰乱血管活性因子的分泌，导致肾小管缺血。
Background Impaired glucose tolerance (IGT) is an important prediabetic stage characterized by elevated concentrations of glucose and insulin in the blood. The pathological hyperglycemia and hyperinsulinemia in IGT may regulate the expression of microRNA-21 (miR-21) and affect the downstream insulin signaling pathways, leading to endothelial cell dysfunction and early renal damage. Methods The individual and combined effects of insulin and glucose were investigated using human glomerular endothelial cells (HGECs). The expression levels of miR-21, and PTEN/AKT/eNOS and MAPK/ET-1 pathway proteins in the treated cells were measured. The levels of nitric oxide (NO) and endothelin-1 (ET-1) secreted by the cells were also measured. The role of miR-21 in mediating the regulatory effects of insulin and glucose was assessed by overexpression/inhibition of this miRNA using mimics/inhibitor. Results High (>16.7 mmol/L) concentration of glucose upregulated the expression of miR-21, leading to the activation and inhibition of the PTEN/AKT/eNOS and MAPK/ET-1 pathways, and upregulation of NO and downregulation of ET-1 secretion, respectively. High (>25 ng/mL) concentration of insulin downregulated the expression of miR-21, and lead to the activation of the MAPK/ET-1 and inhibition of the PTEN/AKT/eNOS pathway, thereby upregulating the expression of ET-1 and downregulating the secretion of NO. MiR-21 was observed to play a key role by directly controlling the activation of the insulin signaling pathways when the cells were cotreated with different concentrations of insulin and glucose. The expression of miR-21 was found to be dependent on the relative concentration of insulin and glucose. Under simulated conditions of the IGT stage (8.3 mmol/L glucose + 50 ng/mL insulin), the inhibitory effect of high insulin concentration on miR-21 expression in the cells attenuated the activation by high glucose concentration, resulting in the downregulation of miR-21, upregulation of ET-1 and downregulation of NO secretion. Conclusion Taken together, these results indicate that high insulin and glucose concentrations regulate the secretory function of glomerular endothelial cells in opposite ways by regulating the expression of miRNA-21. Pathological concentrations of insulin and glucose in the IGT stage may lead to a decrease in miR-21 expression, thereby disordering the secretion of vasoactive factors, resulting in renal tubule ischemia.
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影响因子：
37.8
作者：
Cardillo, C;Nambi, SS;Panza, JA
通讯作者：
Panza, JA
DOI：
10.1007/s10840-012-9777-z
发表时间：
2013-06-01
影响因子：
1.8
作者：
Chan, Yap-Hang;Siu, Chung-Wah;Tse, Hung-Fat
通讯作者：
Tse, Hung-Fat
影响因子：
3.4
作者：
Maria Gamez-Mendez, Ana;Vargas-Robles, Hilda;Escalante, Bruno
通讯作者：
Escalante, Bruno
影响因子：
2.5
作者：
Komala, Muralikrishna Gangadharan;Gross, Simon;Panchapakesan, Usha
通讯作者：
Panchapakesan, Usha
高胰岛素血症通过 mir-7977/SIRT3 信号传导导致葡萄糖耐量受损诱导的肾损伤
影响因子：
3.5
作者：
Gao, Zhongai;Wang, Ziyan;Chang, Baocheng
通讯作者：
Chang, Baocheng