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Abstract: TH-PO913

Uremic Toxin Decreases Intestinal Defense Peptides and Barrier Functions in Chronic Renal Failure Mice

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Satoh, Minoru, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Itano, Seiji, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Kondo, Megumi, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Wada, Yoshihisa, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Kadoya, Hiroyuki, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Sasaki, Tamaki, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Kashihara, Naoki, Kawasaki Medical School, Kurashiki, Okayama, Japan
Background

Alterations of intestinal bacterial flora and intestinal barrier function in chronic kidney disease (CKD) have been reported to affect on uremic toxin influx. However, alteration mechanisms of microbiota and intestinal barrier have not been elucidated. Antimicrobial peptide contributes to maintenance of microbiota. We examined whether uremic toxin decreases intestinal antimicrobial peptide and barrier function in chronic renal failure model mice.

Methods

We used male ICR-derived glomerulonephritis (ICGN) mice for renal failure group. Gene expression in ascending colon was analyzed by microarray analysis and quantitative real-time PCR (qPCR). Gene expression patterns of a whole bacterial flora in the intestine were analyzed by terminal restriction fragment length polymorphism analysis method. Fecal and serum bacteria products (phenol, para-cresol, indole/indole sulfateand skatole) were examined by quantitative chemical analysis. In vitro experiment, Caco-2 cells were exposed to indoxyl sulphate at clinically relevant concentrations (0.1-0.5 mM). Expressions of defensins and tight junction molecules were analyzed by qPCR and ELISA.

Results

Microarray analysis showed antimicrobial peptide, defensin, significantly decreased in ICGN mice. Defensin alfa1 and beta1 mRNA expressions in ascending colon were reduced in ICGN mice compared with control mice. The ratio of pathogenic bacteria clostridia was increased, and the ratio of opportunistic pathogen bacteroides was decreased in intestinal bacterial flora of ICGN mice. Fecal bacteria products phenol and para-cresol were increased in feces of ICGN mouse. Barrier function associated molecules, such as C-type lectin and tight junction, were significantly decreased in ICGN. Intestinal permeability in ICGN was increased compared to ICR mice. Indoxyl sulphate significantly decreased the expressions of C-type lectin and tight junction in Caco2 cells. Indoxyl sulphate also significantly decreased defensin mRNA and protein expression in Caco2 cells.

Conclusion

Uremic toxin decreases intestinal antimicrobial peptides which induce gut microbiome alteration in CKD. Uremic toxin also decreases intestinal barrier function molecules which increase Intestinal permeability in CKD. Both are combined and contribute to the loss of intestinal barrier function in CKD.

Funding

  • Government Support - Non-U.S.