LONP1通过维持线粒体稳态改善终末期肾病相关的血管损伤

尿毒症毒素是导致CKD心血管疾病的重要因素，但具体机制尚不清楚。LONP1在维持线粒体稳态中起重要作用，其在CKD相关血管损伤中的作用尚无研究报道。预实验发现LONP1在5/6Nx小鼠血管组织及IS处理的血管内皮细胞中表达上调，敲低LONP1加重了IS诱导的线粒体损伤及细胞凋亡，而过表达LONP1则减轻了上述现象。生物信息学分析提示PEA3是LONP1上游的转录调控因子，过表达PEA3可增加LONP1的转录和翻译。推测：在CKD，IS等可导致血管细胞线粒体损伤及功能障碍，促进血管损伤；同时PEA3/LONP1通路代偿性上调，但仍不足以有效维持线粒体稳态；通过外源性上调或激活LONP1则能够更为有效的保护线粒体、减轻血管损伤。本项目将从整体、细胞和分子层面阐明PEA3/LONP1在调控线粒体稳态、改善CKD相关的血管损伤中的作用及机制。

Cardiovascular disease is the most common cause of death in CKD patients. Accumulation of uremic toxins is the important pathogenic factor leading to cardiovascular disease in CKD, while the pathogenic mechanism remains nuclear. LONP1 plays a key role in maintaining mitochondrial homeostasis, while its role in vascular injury associated with CKD has not been studied. In our preliminary study, we observed that the expression of LONP1 was upregulated in the vascular tissue of 5/6Nx mice, as well as in the mouse aortic vascular endothelial cells (MAECs) treated with indoxyl sulfate (IS). Interestingly, silencing LONP1 aggravated mitochondrial injury and cell apoptosis induced by IS in MAECs, while overexpression of LONP1 in MAECs protected mitochondria and cells challenged with IS, suggesting a protective role of LONP1 in vascular injury associated with CKD. Meanwhile, bioinformatics analysis predicts 5 binding sites of transcription factor PEA3 in LONP1 promoter region, and overexpression of PEA3 enhanced the mRNA and protein levels of LONP1 in MAECs. In agreement with the upregulation of LONP1, the protein level of PEA3 was also upregulated in the vascular tissue of 5/6Nx mice. Above data suggested that PEA3 might be an upstream regulator of LONP1. These preliminary results highly suggest that PEA3 may regulate LONP1 expression to maintain the mitochondrial homeostasis and protect vascular cells under the CKD condition. However, the compensative increment of PEA3/LONP1 signaling is not enough to antagonize CKD-related damage to mitochondria and endothelial cells. Exogenous upregulation or activation of LONP1 can exert more action on maintaining mitochondrial homeostasis and protecting vascular cells, which finally benefits the cardiovascular system in CKD patients. In this proposal, besides a full study on the role of PEA3/LONP1/mitochondria in CKD-associated vascular injury using models of animals, cells, and molecules, we will also screen LONP1 specific agonists to test a translational potential.