Abstract | BACKGROUND: METHODS:
Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect. RESULTS:
Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 μg/kg in the adenine-induced RF mouse model. At a high concentration of 100 μg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-β, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the 'leaky gut' in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels. CONCLUSION:
Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut-cardio-renal axis.
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Authors | Fumika Nanto-Hara, Yoshitomi Kanemitsu, Shinji Fukuda, Koichi Kikuchi, Kei Asaji, Daisuke Saigusa, Tomoyuki Iwasaki, Hsin-Jung Ho, Eikan Mishima, Takehiro Suzuki, Chitose Suzuki, Tomoya Tsukimi, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Yukako Akiyama, Shigeo Kure, Yuji Owada, Yoshihisa Tomioka, Tomoyoshi Soga, Sadayoshi Ito, Takaaki Abe |
Journal | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
(Nephrol Dial Transplant)
Vol. 35
Issue 2
Pg. 250-264
(02 01 2020)
ISSN: 1460-2385 [Electronic] England |
PMID | 31411705
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. |
Chemical References |
- Guanylyl Cyclase C Agonists
- Peptides
- Guanylate Cyclase
- Adenine
- linaclotide
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Topics |
- Adenine
(toxicity)
- Animals
- Cardio-Renal Syndrome
(chemically induced, drug therapy, metabolism, pathology)
- Disease Models, Animal
- Disease Progression
- Fibrosis
(chemically induced, drug therapy, metabolism, pathology)
- Gastrointestinal Microbiome
(drug effects)
- Guanylate Cyclase
(chemistry)
- Guanylyl Cyclase C Agonists
(pharmacology)
- Inflammation
(chemically induced, drug therapy, metabolism, pathology)
- Male
- Mice
- Mice, Inbred C57BL
- Peptides
(pharmacology)
- Renal Insufficiency, Chronic
(chemically induced, drug therapy, metabolism, pathology)
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