Abstract: SA-PO755
A Guanylate Cyclase C Agonist Linaclotide Reduces Trimethylamine N-Oxide in an Adenine-Induced CKD Model
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Hara, Fumika, Tohoku University Graduate School of Medicine, Sendai, Japan
- Kanemitsu, Yoshitomi, Tohoku University Graduate School of Pharmacutical Sicineces, Sendai, Japan
- Kikuchi, Koichi, Tohoku University Graduate School of Medicine, Sendai, Japan
- Saigusa, Daisuke, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Mishima, Eikan, Tohoku University Graduate School of Medicine, Sendai, Japan
- Suzuki, Takehiro, Tohoku University Graduate School of Medicine, Sendai, Japan
- Soga, Tomoyoshi, Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
- Tomioka, Yoshihisa, Tohoku University Graduate School of Pharmacutical Sicineces, Sendai, Japan
- Fukuda, Shinji, Keio University, Tsuruoka, Japan
- Abe, Takaaki, Tohoku University Graduate School of Medicine, Sendai, Japan
Background
Cardiorenal syndrome is a major cause of mortality in CKD patients. Trimethylamine-N-oxide (TMAO),which is a hepatic metabolized product of trimethylamine (TMA) generated from dietary phosphatidylcholine or carnitine derived by gut microbiota, directly linked to the progression of cardiovascular disease and renal dysfunction. Therefore, targeting TMAO may be one of a novel strategy for the prevention of CVD and CKD.
Methods
A guanylate cyclase C agonist linaclotide was administered to adenine-induced renal failure model and the changes of renal function and gut-derived uremic toxins as well as gut microbiota community were analyzed using metabolomic and metagenomic analyses.
Results
Linaclotide decreased the plasma TMAO level at a clinically used dose (10 μg/kg) in an adenine-induced renal failure mouse. In additon, linaclotide (100 μg/kg), significanlty improved renal function and reduced various uremic toxins.
Linaclotide reduced renal inflammation and fibrosis, cardiac fibrosis as well as collagen I, TGF-β, galectin-3 and ST2 gene expressions.
The plasma galectin-3 and ST2 were also reduced.
In the small intestinal crypt, F4/80-positive macrophages were abundant in renal failure and theexpression was decreased by linaclotide. Reduced colonic claudin1 was also restoredby linaclotide, suggesting that linaclotide ameliorated “leaky-gut” in the renal failure. By metagenome analysis, microbial order Clostridiales may have been responsible for the change in TMAO.
Conclusion
Linaclotide reduced TMAO and uremic toxin levelsand be a potent tool for the cardio-renal syndrome by modification of the “gut-cardiorenal axis”
gut-cardiorenal axis
Funding
- Government Support - Non-U.S.