Diabetes is a leading risk factor for development of urinary tract infection (UTI). UTI caused by uropathogenic Escherichia coli (UPEC), and other uropathogens is a common infectious condition affecting millions of people annually. Gliflozins are diabetes medications that achieve normoglycemia by increasing urinary glucose excretion. We tested the effects of dapagliflozin-induced hyperglucosuria on ascending bacterial UTI in a mouse model.
Dapagliflozin or canagliflozin was used to induce hyperglucosuria in non-diabetic adult female mice prior to transurethral inoculation with UPEC or Klebsiella pneumoniae. Glucose, bacterial load, cytokines, neutrophil mobilization, and inflammation during acute and chronic UTI were determined.
Significant increase in UPEC load was observed in the urinary tract of hyperglucosuric mice, compared to controls. Dapagliflozin-treated mice developed bacteremia resulting in UPEC colonization of the spleen and liver at a higher frequency than controls. Chronic UTI in hyperglucosuric mice resulted in an increased incidence of renal abscesses. Histopathological evaluation revealed only modest increases in tissue damage in the urinary bladders, and kidneys of dapagliflozin-treated mice, despite profound increase in bacterial load. There was poor neutrophil mobilization to the urine of hyperglucosuric mice. We also observed a delayed increase of IL-1β in urine, and bladders, and IL-6 in urine of hyperglucosuric mice. Experimental inoculation with K. pneumoniae also revealed higher bacterial burden in the urinary bladder, spleen and liver from dapagliflozin-treated mice, compared to controls.
Collectively, our results indicate that dapagliflozin-induced hyperglucosuria in non-diabetic female mice leads to increased susceptibility to severe UTI, and bacteremia of urinary tract origin. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.