Panatda Saenkham1, Jamie Jennings-Gee2, Braden Hanson1, Nancy D Kock3, L Garry Adams1, Sargurunathan Subashchandrabose1,2. 1. Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA. 2. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 3. Section on Comparative Medicine, Department of Pathology , Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Abstract
AIM: To test the effects of dapagliflozin-induced hyperglucosuria on ascending bacterial urinary tract infection (UTI) in a mouse model. METHODS: Dapagliflozin or canagliflozin was used to induce hyperglucosuria in non-diabetic adult female mice prior to transurethral inoculation with uropathogenic Escherichia coli (UPEC) or Klebsiella pneumoniae. Glucose, bacterial load, cytokines, neutrophil mobilization and inflammation during acute and chronic UTI were determined. RESULTS: Significant increase in UPEC load was observed in the urinary tract of hyperglucosuric mice compared with controls. Dapagliflozin-treated mice developed bacteraemia 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 a 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 with controls. CONCLUSION: Collectively, our results indicate that dapagliflozin-induced hyperglucosuria in non-diabetic female mice leads to increased susceptibility to severe UTI, and bacteraemia of urinary tract origin.
AIM: To test the effects of dapagliflozin-induced hyperglucosuria on ascending bacterial urinary tract infection (UTI) in a mouse model. METHODS:Dapagliflozin or canagliflozin was used to induce hyperglucosuria in non-diabetic adult female mice prior to transurethral inoculation with uropathogenic Escherichia coli (UPEC) or Klebsiella pneumoniae. Glucose, bacterial load, cytokines, neutrophil mobilization and inflammation during acute and chronic UTI were determined. RESULTS: Significant increase in UPEC load was observed in the urinary tract of hyperglucosuric mice compared with controls. Dapagliflozin-treated mice developed bacteraemia 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 a 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 with controls. CONCLUSION: Collectively, our results indicate that dapagliflozin-induced hyperglucosuria in non-diabetic female mice leads to increased susceptibility to severe UTI, and bacteraemia of urinary tract origin.
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Authors: Panatda Saenkham-Huntsinger; Amanda N Hyre; Braden S Hanson; George L Donati; L Garry Adams; Chanelle Ryan; Alejandra Londoño; Ahmed M Moustafa; Paul J Planet; Sargurunathan Subashchandrabose Journal: mBio Date: 2021-09-07 Impact factor: 7.867
Authors: Lisa L Abler; Chelsea A O'Driscoll; Sara A Colopy; Kimberly P Keil Stietz; Peiqing Wang; Zunyi Wang; Faye Hartmann; Stephanie M Crader-Smith; Jonathan N Oellete; Vatsal Mehta; Steven R Oakes; Matthew D Grimes; Gordon S Mitchell; Mieke Baan; Shannon J Gallagher; Dawn B Davis; Michelle E Kimple; Dale E Bjorling; Jyoti J Watters; Chad M Vezina Journal: Am J Physiol Renal Physiol Date: 2021-06-14