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

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

  • Redox Biol. 2025 Dec:88:103929. doi: 10.1016/j.redox.2025.103929.
Xiaolu Zhang 1,  Shuzhen Li 2,  Shanshan Li 3,  Bing Liu 3,  Guixia Ding 3,  Mengqiu Wu 3,  Yue Zhang 3,  Songming Huang 3,  Wei Gong 4,  Zhanjun Jia 5,  Aihua Zhang 6
Affiliations

Affiliations

  • 1 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Lab of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China; Department of Child Health Care, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
  • 2 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Lab of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China. Electronic address: [email protected].
  • 3 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Lab of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China.
  • 4 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Lab of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China. Electronic address: [email protected].
  • 5 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Lab of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China. Electronic address: [email protected].
  • 6 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Lab of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, China. Electronic address: [email protected].
PMID: 41275592 DOI: 10.1016/j.redox.2025.103929
Abstract

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 in glomerulosclerosis and CKD progression. Taken together, our findings identify LONP1 as a therapeutic target for balancing glomerular redox, alleviating inflammation, and retarding glomerulosclerosis.

Keywords

Endothelial cell; Glomerulosclerosis; LONP1; Redox balance; SOD2.

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