Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model.

Abstract

Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.

• Authors: Eikan Mishima, Shinji Fukuda, Yoshitomi Kanemitsu, Daisuke Saigusa, Chikahisa Mukawa, Kei Asaji, Yotaro Matsumoto, Hiroki Tsukamoto, Tatsuki Tachikawa, Tomoya Tsukimi, Noriko N Fukuda, Hsin-Jung Ho, Koichi Kikuchi, Chitose Suzuki, Fumika Nanto, Takehiro Suzuki, Sadayoshi Ito, Tomoyoshi Soga, Yoshihisa Tomioka, Takaaki Abe
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 315 Issue 4 Pg. F824-F833 (10 01 2018) ISSN: 1522-1466 [Electronic] United States
• PMID: 29167170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Sodium-Glucose Transporter 2 Inhibitors
• Toxins, Biological
• Canagliflozin

Topics

• Animals
• Canagliflozin (pharmacology)
• Disease Models, Animal
• Gastrointestinal Microbiome (drug effects)
• Gastrointestinal Tract (drug effects)
• Male
• Mice, Inbred C57BL
• Renal Insufficiency, Chronic (blood, drug therapy)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology)
• Toxins, Biological (blood, pharmacology)
• Uremia (blood, drug therapy)