Abstract: SA-PO128
GATM Ameliorates the Acute-to-Chronic Kidney Disease Transition through Enhancing Endogenous Creatine-Mediated Lipophagy
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Guan, Xu, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, Chongqing, China
- Li, Fan, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, Chongqing, China
- Xiong, Weijian, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, Chongqing, China
Background
Acute kidney injury (AKI), characterized by a rapid decline of kidney function in the short term, is a common clinical syndrome with complex pathogenesis.The incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). GATM, highly expressed in the mitochondria of renal tubular epithelial cells (RTECs), is a key rate-limiting enzyme in the endogenous creatine biosynthesis. Previous studies have found mutations in GATM gene in the kidney of patients with CKD contribute to the ROS production, mitochondrial damage and cell death in RTECs. Moreover, GATM mutations also upregulate the expression of the fibrotic cytokine IL-18 and accelerate CKD progression, indicating that GATM may play an important role in the pathogenesis of kidney diseases. However, the role of GATM in AKI-to-CKD transition remains unknown.
Methods
In this study, GATM adenovirus-overexpressed mice and cultured RTECs were used as subjects. Renal ischemia-reperfusion (IRI) mouse model, RNA sequencing, Immunofluorescence, Western blot and qRT-PCR were employed to reveal the crucial role and mechanisms of GATM in AKI-to-CKD transition.
Results
GATM was significantly reduced in the kidneys AKI patients and IRI mice. The analysis indicated GATM expression was positively correlated with kidney function. In vivo, GATM overexpression by adenovirus improved the transition from AKI to CKD. Primary RTECs were employed to RNA-seq analysis that GATM overexpression upregulated the expression of fatty acid degradation and autophagy-related genes while downregulated lipid droplet-related gene in RTECs through KEGG analysis. Transmission electron microscopy revealed that a large amount of lipid droplets were accumulated in RTECs after IRI, which could be reversed by GATM overexpression, accompanied by an increased autophagosomes enveloping-lipid droplets and reduced kidney injury. GATM promoted endogenous creatine synthesis and enhanced the lipophagy of RTECs. Collectively, our findings demonstrate that GATM deficiency contributes to AKI-to-CKD transition and GATM ameliorates AKI-to-CKD transition though enhancing endogenous creatine-mediated lipophagy.
Conclusion
GATM plays an important role in the transition of AKI to CKD and targeting GATM-lipophagy axis could serve as a promising therapeutic approach for retarding AKI-to-CKD transition.