Abstract: SA-PO380

The Impact of Canagliflozin on the Gut Microbiota of Non-Diabetic CKD Rats and Its Effect on Cardiovascular System

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Matsui, Ayumi, Keio University school of medicine, Tokyo, Japan
  • Yoshifuji, Ayumi, KEIO UNIVERSITY, Tokyo, Japan
  • Irie, Junichiro, Keio University School of Medicine, Tokyo, Japan
  • Tajima, Takaya, Keio University school of medicine, Tokyo, Japan
  • Uchiyama, Kiyotaka, Keio University, School of Medicine, Tokyo, Japan
  • Ito, Tomoaki, Keio University , Tokyo-to, Japan
  • Wakino, Shu, Keio University , Tokyo-to, Japan
  • Itoh, Hiroshi, Keio University School of Medicine, Tokyo, Japan
Background

The gut is responsible for the production of some uremic toxins by microbiota which induces the tissue damages in chronic kidney disease (CKD). Gut microbiota population was reported to be aberrated in CKD. Novel anti-diabetic reagent sodium glucose cotransporter (SGLT)2 inhibitor, canagliflozin(Cana) harbors a marginal inhibitory potential to gut-type SGLT1, which is hypothesized to affect the dysbiosis in CKD. We investigated the impact of Cana on the microbiota and on cardiovascular and renal tissues in non-diabetic CKD rats.

Methods

6-week-old male spontaneously-hypertensive rats (SHRs) were randomly assigned to three experimental groups; sham operated SHR (Sham), 5/6 nephrectomized SHR (Nx), and 5/6 nephrectomized SHR treated with Cana (0.024% mixed in standard chow) (Nx+C). After 12weeks, microbiota population was examined by T-RFLP and following PCR. The tissue findings and molecular changes of kidney, cardiovascular systems and intestine were also investigated.

Results

Proteinuria, serum creatinine and BUN levels were significantly elevated in Nx group, although Cana failed to improve the impaired renal function. Serum concentrations of gut-derived uremic toxins such as indoxyl sulfate and hippuric acid were significantly elevated in Nx rats, which were lowered by Cana. The population of gut microbiota was changed in Nx rats, which were restored by Cana. Quantitative analysis of Lactobacillus species confirmed a significant decrease of Lactobacillus by Nx, which was also reversed by Cana. Immunoblotting analysis of the tight junction proteins of colonic tissue confirmed that Cana restored claudin-1, occludin, and Zo1 expression which were downregulated in Nx rats . Nx rats showed significantly increased wall thickness of the thoracic aorta and cardiac intestinal fibrosis. CTGF and TGFβ1 mRNA expression in cardiac tissues were significantly increased by Nx. These changes were ameliorated by Cana.

Conclusion

Cana successfully reduced serum indoxyl sulfate and hippuric acid levels by restoring dysbiosis in non-diabetic CKD rats, which might have favorable effects on cardiovascular systems in CKD condition.