Deficiency of Leucine-Rich α2-Glycoprotein 1 Suppresses Kidney Fibrosis Caused by Ischemia-Reperfusion Injury

Background: Acute kidney injury (AKI) is recognized for its potential to progress into chronic kidney disease (CKD), a transition known as AKI to CKD. Developing strategies to manage this progression is crucial. Ischemia-reperfusion injury (IRI) serves as a model for AKI and is known to lead to renal fibrosis over time, primarily through the TGF-β pathway. Leucine-rich alpha-2-glycoprotein 1 (LRG1) is endogenously expressed in renal tubular epithelial cells and regulates renal fibrosis by modulating the TGF-β/Smad3 signaling pathway (Kidney Int, 2022). Additionally, LRG1 silencing attenuates AKI following IRI by regulating autophagy and apoptosis via the TGFβ1-Smad1/5 signaling pathway (Arch Biochem Biophys, 2024). However, the role of LRG1 during the remodeling phase of IRI remains unclear. This study investigates the functional role of LRG1 in the AKI to CKD transition using the IRI model in systemic LRG1 knockout (KO) mice. Methods: Experiment 1: Unilateral IRI was performed on wild-type (WT) 6- to 8-week-old male C57BL/6 mice. Ischemia was induced by a retroperitoneal approach to the left kidney using an atraumatic vascular clip for 30 minutes. Mice were sacrificed at 2, 7, 14, and 28 days after surgery to evaluate renal histological findings and LRG1 expression. Experiment 2: Male LRG1 KO mice and their littermate control (LC) mice, aged 6-8 weeks, underwent unilateral IRI. They were sacrificed on days 2, 7, and 28 post-surgery for renal histological comparison. Results: Experiment 1:LRG1 mRNA expression in the kidney was significantly higher on the operated side than on the sham side throughout the period, peaking on day 7 and then gradually decreasing. Experiment 2: LRG1 KO mice exhibited significantly reduced renal fibrosis area compared to LC mice on day 28. Furthermore, renal mRNA expression levels of collagen type 1 and type 3 , as well as TGFβ, were lower in LRG1 KO mice than in LC mice on day 28 postoperatively, concomitant with the suppression of TGF-β signaling pathway. Conclusion: Renal LRG1 expression was persistently upregulated until the remodeling phase after IRI. LRG1 knockout mice showed suppression of chronic fibrosis post-IRI and a reduction in TGF-β signaling. Therefore, LRG1 is implicated in the pathogenesis of the AKI to CKD transition and represents a potential therapeutic target. Funding: Government Support – Non-U.S.