内质网Pannexin-1蛋白通过钙离子/NFATc3/miR23a调控细胞衰老介导急性肾损伤后慢性肾脏病进展的机制研究

急性肾损伤（AKI）是导致慢性肾脏病（CKD）的重要原因。既往研究已证实存在“AKI→肾脏细胞衰老→肾间质纤维化”的CKD进展途径，细胞衰老在CKD进展中具有重要作用。Pannexin-1（Panx-1）是一种膜蛋白，在细胞损伤时表达上调，已证实阻断Panx-1可减轻AKI，但对于Panx-1是否可调控细胞衰老尚无报道。我们的前期研究显示损伤所致高表达的Panx-1位于内质网膜并可上调胞内游离钙离子含量，高表达的Panx-1还可致细胞核核膜屏障受损及胞核双链DNA进入胞浆，进而激活cGAS-STING通路引发细胞衰老。据此我们提出内质网Panx-1可上调胞内游离钙离子水平致核膜屏障受损及细胞衰老这一假说。为证实该假说，本项目将从细胞模型、动物模型及肾活检组织多个层面进行研究，探讨能否通过干预Panx-1减轻肾脏细胞衰老及延缓AKI后CKD进展，为干预AKI后CKD进展提供新的靶点。

Acute kidney injury (AKI) is a major cause of chronic kidney disease (CKD). Previous studies have demonstrated a progression from AKI to CKD, in which senescence play an important role. Pannexin-1 (Panx-1) is a membrane protein and can be upregulated during stress. Blocking Panx-1 can ameliorate AKI. It is unclear whether Panx-1 is connected with senescence. Our preliminary studies found that Panx-1 could be detected in endonulear reticulum and could control the concentration of calcium in cytoplasm. We also found that Panx-1 up regulation could cause the interruption of the nuclear shield. Therefore, double strain DNA could exgraft from nucleus and activate cGAS-STING to induce senescence. Based on these findings, we hypothesize that the upregulation of Panx-1 in ER can increase free calcium in cytoplasm to interrupt nuclear shield and cause senescence. To support our hypothesis, we will investigate by various experiments including in vivo, in vitro, and clinical study. We hope to find a new target for treating CKD post-AKI and reduce the progression of CKD post-AKI.