Abstract: FR-PO1212
Glutamine Reprograms Metabolism in CKD-Induced Pathological Cardiac Remodeling via the GLS1/GLUD1 Axis
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Bai, Linnan, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
- Wang, Yi, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Kang, Minchao, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
- Li, Qiu-yu, Zhejiang University School of Medicine Children's Hospital, Hangzhou, Zhejiang, China
- Wu, Junnan, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
Background
CKD-induced cardiac remodeling is characterized by myocardial hypertrophy, however, available therapeutic options are limited. Here, we employed a multi-omics approach to analyze a total of 36 mice hearts to detect cardiac structural changes.
Methods
We performed 5/6 nephrectomy surgery on mice and collected samples at multiple time points during disease progression (6, 12, and 18 weeks post-surgery). Initially, we performed snRNA-seq and a comprehensive metabolomics strategy including in situ metabolomic was conducted to obtain the in situ metabolic profiles. We screened out the most significantly changed metabolic pathway and corresponding rate-limiting enzymes. Using targeted metabolomics and Western blotting, we validated metabolic reprogramming signatures. We further created CKD mice with conditional knockout of the rate-limiting enzyme in cardiomyocytes and monitored the degree of cardiac tissue damage.
Results
Our findings illustrate the time course of changing gene expression patterns for multiple CKD stages. The TCA cycle was defective in the chronic phase but was transiently activated in the very early stages of CKD. The glutaminolysis pathway, however, was persistently activated throughout the time course and reached a peak at 18 weeks post-surgery, especially in left ventricle and interventricular septum region. Our gene-metabolite interaction network showed that glutaminase 1 (GLS1), the rate-limiting enzyme in glutaminolysis, and its target gene glutamate dehydrogenase 1 (GLUD1) were activated and up-regulated in CKD cardiomyocytes. Cardiac-specific deletion of GLS1 was achieved, and this ameliorated cardiac dysfunction and cardiomyocyte hypertrophy in response to CKD. At the mechanistic level, GLS1 controls the epigenetic expression of pro-hypertrophic genes. Moreover, GLS1 and GLUD1 are both transaminases, leading to the accumulation of ammonia in mitochondria.
Conclusion
These findings suggested the GLS1/GLUD1 axis plays an essential role in maintaining a homeostatic metabolic response in cardiomyocytes under CKD.
Funding
- Government Support – Non-U.S.