Endothelial Lon protease 1 facilitates the redox balance to prevent glomerulosclerosis by acting on superoxide dismutase 2 ubiquitination

作者：Xiaolu Zhang, Shuzhen Li, Shanshan Li, Bing Liu, Shanshan Li, Bing Liu, Guixia Ding, Mengqiu Wu, Yue Zhang, Songming Huang, Wei Gong, Zhanjun Jia, Aihua Zhang · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103929 · 被引用次数：6 · 研究领域：Mitochondrial Function and Pathology、Renal Diseases and Glomerulopathies、Chronic Kidney Disease and Diabetes

Endothelial injury is an early event in chronic kidney disease (CKD) leading to renal hemodynamic disorders and even glomerulosclerosis. During this process, both oxidative stress and inflammation originating from injured endothelial cells can initiate pathogenic cell-to-cell interactions via a paracrine mechanism. Accumulating evidence underscores the pivotal role of mitochondrial dysfunction as a crucial mechanism underlying endothelial dysfunction. Lon protease 1 (LONP1) is a mitochondrial protease that plays a key role in maintaining mitochondrial homeostasis; however, its role in endothelial dysfunction-related renal disease is unknown. In CKD patients and mice subjected to 5/6 nephrectomy (5/6Nx), we observed decreased LONP1 expression in glomerular endothelial cells. Interestingly, endothelial cell-specific heterozygous knockout of LONP1 exacerbated glomerulosclerosis and aggravated renal function decline, proteinuria, hypertension and kidney inflammation in 5/6Nx mice. Mechanistically, our results suggest that the loss of LONP1 strikingly increased reactive oxygen species (ROS) levels by promoting the ubiquitination of mitochondrial superoxide dismutase 2 (SOD2); which in turn led to mitochondrial dysfunction and inflammation within endothelial cells. Additionally, the increase in mitochondrial ROS and subsequent production of inflammatory cytokines from damaged endothelial cells further trigger mesangial cell proliferation and podocyte injury, which together result i...