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Updated: Jul 30, 2025
A Mouse 5/6th Nephrectomy Model That Induces Experimental Uremic Cardiomyopathy
Published on: November 7, 2017
Cyclic GMP-AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil
Nattavong Suksawad1, Kanyarat Udompornpitak1, Natchapon Thawinpipat1
1Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok 10330, Thailand.
Abstract:
Uremia-induced systemic inflammation is partly caused by the dissemination of microbial molecules such as lipopolysaccharide and bacterial double-stranded DNA from leaked gut damaged by immune cells in response to the microbial molecules. Cyclic GMP-AMP synthase (cGAS) can recognize fragmented DNA and induce cGAMP synthesis for the activation of the stimulator of interferon genes (STING) pathway. To study the effect of cGAS in uremia-induced systemic inflammation, we performed bilateral nephrectomy (BNx) in wild-type and cGAS knock-out mice and found that the gut leakage and blood uremia from both groups were similar. However, serum cytokines (TNF-α and IL-6) and neutrophil extracellular traps (NETs) decreased significantly in cGAS-/- neutrophils after stimulation with LPS or bacterial cell-free DNA. Transcriptomic analysis of LPS-stimulated cGAS-/- neutrophils also confirmed the down-regulation of neutrophil effector functions. The extracellular flux analysis showed that cGAS-/- neutrophils exhibited a higher respiratory rate than wild-type neutrophils despite having similar mitochondrial abundance and function. Our results suggest that cGAS may control effector functions and the mitochondrial respiration of neutrophils in response to LPS or bacterial DNA.
Insights
Cyclic GMP-AMP synthase (cGAS) plays a role in uremia-induced inflammation. cGAS deficiency in neutrophils reduced inflammatory responses and altered mitochondrial respiration, suggesting cGAS regulates neutrophil function.
Area of Science:
- Immunology
- Molecular Biology
- Renal Medicine
Background:
- Uremia causes systemic inflammation via microbial molecule dissemination from gut leakage.
- The Cyclic GMP-AMP synthase (cGAS)-STING pathway recognizes microbial DNA and triggers immune responses.
- Neutrophils are key immune cells involved in inflammatory processes.
Purpose of the Study:
- To investigate the role of cGAS in uremia-induced systemic inflammation.
- To determine how cGAS deficiency affects neutrophil function and inflammatory markers in a uremia model.
Main Methods:
- Bilateral nephrectomy (BNx) was performed on wild-type and cGAS knockout mice.
- Neutrophils were isolated and stimulated with lipopolysaccharide (LPS) or bacterial DNA.
- Serum cytokines, neutrophil extracellular traps (NETs), transcriptomic profiles, and extracellular flux were analyzed.
Main Results:
- cGAS knockout mice showed similar uremia and gut leakage compared to wild-type mice.
- Stimulation of cGAS-deficient neutrophils with LPS or DNA led to decreased serum cytokines (TNF-α, IL-6) and NETs.
- Transcriptomic analysis revealed down-regulated neutrophil effector functions in cGAS-deficient neutrophils.
- cGAS-deficient neutrophils exhibited higher respiratory rates than wild-type neutrophils.
Conclusions:
- cGAS deficiency mitigates certain inflammatory responses in a uremia model.
- cGAS influences neutrophil effector functions and mitochondrial respiration in response to microbial stimuli.
- These findings highlight cGAS as a potential therapeutic target for managing inflammation in uremia.
