TY - JOUR
T1 - Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model
AU - Mishima, Eikan
AU - Fukuda, Shinji
AU - Kanemitsu, Yoshitomi
AU - Saigusa, Daisuke
AU - Mukawa, Chikahisa
AU - Asaji, Kei
AU - Matsumoto, Yotaro
AU - Tsukamoto, Hiroki
AU - Tachikawa, Tatsuki
AU - Tsukimi, Tomoya
AU - Fukuda, Noriko N.
AU - Ho, Hsin Jung
AU - Kikuchi, Koichi
AU - Suzuki, Chitose
AU - Nanto, Fumika
AU - Suzuki, Takehiro
AU - Ito, Sadayoshi
AU - Soga, Tomoyoshi
AU - Tomioka, Yoshihisa
AU - Abe, Takaaki
N1 - Funding Information:
This work was supported in part by JSPS KAKENHI (16K19474 to E. Mishima; 16H04901 and 17H05654 to S. Fukuda; 26670070 to T. Abe), JST PRESTO (JPMJPR1537 to S. Fukuda), the Japan Foundation for Applied Enzymology, and HIROMI Medical Research Foundation.
Funding Information:
This work was supported by the Mitsubishi Tanabe Pharma Corporation.
PY - 2018/10
Y1 - 2018/10
N2 - Mishima E, Fukuda S, Kanemitsu Y, Saigusa D, Mukawa C, Asaji K, Matsumoto Y, Tsukamoto H, Tachikawa T, Tsukimi T, Fukuda NN, Ho HJ, Kikuchi K, Suzuki C, Nanto F, Suzuki T, Ito S, Soga T, Tomioka Y, Abe T. Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model. Am J Physiol Renal Physiol 315: F824–F833, 2018. First published November 22, 2017; doi:10.1152/ajprenal.00314.2017.—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.
AB - Mishima E, Fukuda S, Kanemitsu Y, Saigusa D, Mukawa C, Asaji K, Matsumoto Y, Tsukamoto H, Tachikawa T, Tsukimi T, Fukuda NN, Ho HJ, Kikuchi K, Suzuki C, Nanto F, Suzuki T, Ito S, Soga T, Tomioka Y, Abe T. Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model. Am J Physiol Renal Physiol 315: F824–F833, 2018. First published November 22, 2017; doi:10.1152/ajprenal.00314.2017.—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.
KW - Microbiota
KW - P-cresyl sulfate
KW - Short-chain fatty acids
KW - Sodium glucose transporter
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U2 - 10.1152/ajprenal.00314.2017
DO - 10.1152/ajprenal.00314.2017
M3 - Article
C2 - 29167170
AN - SCOPUS:85052302177
SN - 0363-6127
VL - 315
SP - F824-F833
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 4
ER -