Du Junpei, Yang Yuxin, Rao Jingan, Ma Xiaoqian, Tang Shanshan, Liu Jian, Liu Yeqing, Liu Shipan, Li Guodong, Liang Shangdong, Gao Yun
School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
Second Clinical Medical College, Nanchang University, Nanchang, 330006, China.
Mol Neurobiol. 2025 Mar 27. doi: 10.1007/s12035-025-04883-9.
Diabetic cardiac autonomic neuropathy (DCAN) represents a significant and prevalent complication of diabetes. Further research is required to ascertain the role of the P2Y12 receptor, which is expressed on macrophages and satellite glial cells (SGCs), in the pathophysiology of DCAN. The objective of this study was to ascertain whether resident macrophages in the superior cervical ganglion (SCG) are involved in the pathological changes associated with DCAN, which are mediated by the P2Y12 receptor in satellite glial cells (SGCs). The findings showed that DCAN rats had higher sympathetic nerve discharge activity than the control group. Furthermore, the expression of P2Y12 receptor, glial fibrillary acidic protein (GFAP), macrophage-like targets (colony-stimulating factor 1 receptor (CSF1R), colony-stimulating factor 1 (CSF1)), and interleukin-34 (IL-34) in SCG among DCAN rats was clearly elevated. Moreover, co-expression levels of NeuN and CSF1 in neurons, P2Y12 and GFAP as well as P2Y12 and IBA-1 in SCGs were increased. However, treatment with P2Y12 shRNA led to significant reductions in all above parameters. The action mechanism may involve reducing the expression of P2Y12 receptors in macrophages and SGCs, decreasing the expression of CSF1 in SCG neurons to weaken the CSF1-CSF1R signal, inhibiting the activation of macrophages and SGCs, and reducing the release of inflammatory factors. This ultimately alleviated abnormal neuronal excitation in SCG and maintaining balance in cardiac autonomic nervous activity. Therefore, targeting the P2Y12 receptor to disrupt the resident macrophages participate in pathological changes, may be an effective approach for improving DCAN.
糖尿病性心脏自主神经病变（DCAN）是糖尿病一种严重且常见的并发症。需要进一步研究以确定在巨噬细胞和卫星神经胶质细胞（SGCs）上表达的P2Y12受体在DCAN病理生理学中的作用。本研究的目的是确定颈上神经节（SCG）中的驻留巨噬细胞是否参与与DCAN相关的病理变化，这些变化由卫星神经胶质细胞（SGCs）中的P2Y12受体介导。研究结果表明，DCAN大鼠的交感神经放电活动高于对照组。此外，DCAN大鼠SCG中P2Y12受体、胶质纤维酸性蛋白（GFAP）、巨噬细胞样靶点（集落刺激因子1受体（CSF1R）、集落刺激因子1（CSF1））和白细胞介素-34（IL-34）的表达明显升高。此外，神经元中NeuN和CSF1的共表达水平、SCG中P2Y12和GFAP以及P2Y12和IBA-1的共表达水平均增加。然而，用P2Y12 shRNA治疗导致上述所有参数显著降低。作用机制可能包括降低巨噬细胞和SGCs中P2Y12受体的表达，减少SCG神经元中CSF1的表达以减弱CSF1-CSF1R信号，抑制巨噬细胞和SGCs的激活，以及减少炎症因子的释放。这最终减轻了SCG中异常的神经元兴奋并维持心脏自主神经活动的平衡。因此，靶向P2Y12受体以破坏驻留巨噬细胞参与的病理变化，可能是改善DCAN的有效方法。
