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Iguratimod Alleviates Endothelial to Mesenchymal Transition by Inducing AMBRA1/PARKIN-Dependent Mitophagy and Inhibiting NLRP3 Activation During Renal Allograft Interstitial Fibrosis

Z. Gui1, W. Zijie2, M. Zheng3, R. Tan3, M. Gu4

1Department of Urology, The Second Affiliated Hospital with Nanjing Medical University, Nanjing, China, 2Jiangsu Province Hospital, Nanjing, China, 3Department of Urology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China, 4Department of Urology, the Second Affiliated Hospital with Nanjing Medical University, Nanjing, China

Meeting: 2022 American Transplant Congress

Abstract number: 572

Keywords: Endothelial cells, Fibrosis, Kidney transplantation, Mice

Topic: Basic Science » Basic Clinical Science » 19 - Chronic Organ Rejection

Session Information

Session Name: Chronic Organ Rejection

Session Type: Rapid Fire Oral Abstract

Date: Tuesday, June 7, 2022

Session Time: 5:30pm-7:00pm

 Presentation Time: 5:40pm-5:50pm

Location: Hynes Room 309

*Purpose: Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial- mesenchymal transition (EndMT) is an important source to allograft IF/TA. Iguratimod (IGU) has been reported to widely used to prevent the progression of rheumatism. However, the pharmacological mechanism of IGU in kidney transplantation remains to be determined. The purpose of this study was to explore the effect of mitophagy on CAD and the mechanism of the effect of IGU.

*Methods: We isolated endothelial cells from renal allograft of CAD patients and examine the level of mitophagy and mitochondrial damage. Then, we performed kidney transplantation of Balb/c mice kidneys into C57BL/6 recipients following bilateral nephrectomy to establish CAD mice model. Based on CAD models, we intervened with IGU to explore the effect of IGU on CAD. Hematoxylin-eosin (HE) staining, immunohistochemical and western blot detection were used to observe the pathological changes, level of mitophagy and EndMT in each group. In addition, human renal glomerular endothelial cells (HRGECs) treated with tumor necrosis factor-α (TNF-α) and IGU to examine the role of IGU on TNF-α-induced-EndMT and mitochondrial damage in vivo. Real-time PCR and western blot were used to detect the expression of related genes and proteins. RNA sequencing was used to detect the changes of gene transcriptome level after the treatment with TNF-α and IGU.

*Results: Here, we first found that the changes of mitophagy were increased in the early stages of kidney transplantation but not the late stages in CAD patients and mice. The level of mitochondrial damage increased with the extension of time. Our results also showed that mitophagy was upregulated upon AMBRA1/PARKIN pathway by IGU which could significant reduced expression of TNF-α-induced-EndMT in vivo and vitro. To explore the mechanism behind it, we detected the relationship among IGU, mitophagy and TNF-α-induced-EndMT in HRGECs. Through next-generation sequencing, we found that TNF-α cause mitochondrial damage and stimulate NLRP3 inflammasome activation. This progress promote progression of EndMT and renal allograft interstitial fibrosis, and IGU’s effect on the EndMT was associated with NLRP3 stabilization.

*Conclusions: Impaired mitophagy may aggravate CAD after renal transplantation by promoting EndMT. IGU might protect the HRGECs from the mitochondrial damage induced by NLRP3 triggers culminating through AMBRA1/PARKIN-induced mitophagy activation.

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To cite this abstract in AMA style:

Gui Z, Zijie W, Zheng M, Tan R, Gu M. Iguratimod Alleviates Endothelial to Mesenchymal Transition by Inducing AMBRA1/PARKIN-Dependent Mitophagy and Inhibiting NLRP3 Activation During Renal Allograft Interstitial Fibrosis [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/iguratimod-alleviates-endothelial-to-mesenchymal-transition-by-inducing-ambra1-parkin-dependent-mitophagy-and-inhibiting-nlrp3-activation-during-renal-allograft-interstitial-fibrosis/. Accessed May 30, 2025.

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