P2Y12 shRNA 使 2 型糖尿病大鼠炎症功能障碍的肝葡萄糖激酶活性恢复正常。
P2Y12 shRNA normalizes inflammatory dysfunctional hepatic glucokinase activity in type 2 diabetic rats.
机构信息
Neuropharmacology Laboratory of Physiology Department, Basic Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China.
Undergraduate Student of Clinic Medicine Department, Medical School of Nanchang University, Nanchang, 330006, PR China.
出版信息
Biomed Pharmacother. 2020 Dec;132:110803. doi: 10.1016/j.biopha.2020.110803. Epub 2020 Oct 2.
The celiac ganglion projects its postganglionic (including purinergic) fibers to the liver. P2Y12 receptor is one of the P2Y family members. We found that the expression levels of P2Y12 receptor in both celiac ganglia and liver were increased in type 2 diabetes mellitus (T2DM) rats which also displayed an enhanced activity of celiac sympathetic nerve discharge (SND). In addition, a marked decrease of hepatic glucokinase (GK) expression was accompanied by reduced hepatic glycogen synthesis in T2DM rats, whereas meanwhile the levels of NLRP3, active caspase-1, NF-κB, and interleukin-1β were elevated. All these abnormal alterations could be largely reversed after treatment of short hairpin RNA (shRNA) targeting P2Y12. Our results indicate that the silence of P2Y12 by shRNA may effectively correct the anomalous activity of celiac SND and improve the dysfunctional hepatic glucokinase by counteracting hepatocyte inflammation and likely pyroptosis due to activated NLRP3 inflammasome and caspase-1 signaling, thereby attenuating hyperglycemia in T2DM rats.
腹腔神经节将其节后（包括嘌呤能）纤维投射到肝脏。P2Y12 受体是 P2Y 家族成员之一。我们发现，2 型糖尿病（T2DM）大鼠的腹腔神经节和肝脏中 P2Y12 受体的表达水平均增加，同时腹腔交感神经放电（SND）活性增强。此外，T2DM 大鼠肝葡萄糖激酶（GK）表达明显降低，肝糖原合成减少，而 NLRP3、活性半胱天冬酶-1、NF-κB 和白细胞介素-1β 的水平升高。所有这些异常改变在用短发夹 RNA（shRNA）靶向 P2Y12 治疗后均可得到很大逆转。我们的结果表明，shRNA 沉默 P2Y12 可有效纠正腹腔 SND 的异常活动，并通过拮抗肝细胞炎症和可能由于激活的 NLRP3 炎症小体和半胱天冬酶-1 信号导致的细胞焦亡，改善功能性肝葡萄糖激酶，从而减轻 T2DM 大鼠的高血糖。
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