Objectives: Urinary tract infections (UTIs), commonly caused by uropathogenic Escherichia coli (UPEC), confer significant morbidity among postmenopausal women. Glycosaminoglycans (GAGs) comprise the first line of defense at the bladder's luminal surface. Our objective was to use a murine model of menopause to determine whether estrogen status affects the GAG layer in response to UPEC infection.
Methods: Adult female mice underwent sham surgery (SHAM, n = 18) or oophorectomy (OVX, n = 66) to establish a murine model of menopause. A subset of oophorectomized mice underwent hormone therapy (HT, n = 33) with 17β-estradiol. Mice were inoculated with UPEC and killed at various time points; bladders were collected and GAG layer thickness was assessed in multiple bladder sections. Sixteen measurements were made per bladder. A repeated-measures 2-way analysis of variance was performed to determine the effect of time after infection and hormonal condition on GAG thickness. We also investigated the molecular underpinnings of GAG biosynthesis in response to alterations in estrogen status and infection.
Results: We did not observe significant difference of GAG thickness among the 3 hormonal conditions; however, the time course of GAG thickness was significantly different (P < 0.05). The OVX mice demonstrated significantly greater thickness at 72 hours after infection (P = 0.0001), and this effect was shifted earlier (24 hours after infection) on the addition of HT (P = 0.001). At 2 to 4 weeks after infection, GAG thickness among all cohorts was not significantly different from baseline. In addition, quantitative reverse transcription-polymerase chain reaction analysis revealed that GAG biosynthesis is altered by estrogen status at basal level and on infection.
Conclusions: The GAG layer is dynamically altered during the course of UTI. Our data show that HT positively regulates GAG layer thickness over time, as well as the composition of the GAGs. In addition, the GAG sulfation status can be influenced by estrogen levels in response to UPEC infection. The protective effects of the GAG layer in UTI may represent pharmacologic targets for the treatment and prevention of postmenopausal UTI.