SUFU 2018: Overexpression of Estrogen Receptor Β in Urothelium Protects Against Uropathogenic E. Coli Urinary Tract Infection

Austin, TX ( The host factors in female UTI defense include estrogen. A prior study showed that estrogen’s UTI protective effect on bladder urothelial cells grown in culture (in vitro experiments) was through Estrogen Receptor Β (ERβ) and not ERα.  Dr. Toby Chai and colleagues hypothesize that overexpression of urothelial ERβ in a transgenic mouse would show protection against UTI development (in vivo model).

They used a transgene containing a UPII promoter (urothelial restriction) linked to the ERβ gene was inserted into the C57BL6 mouse (WT) genome to create a urothelially restricted ERβ overexpressing mouse (uERβ-OE+). Female mice, 12 weeks old, were used derived from 3 cohort populations – WT, uERβ-OEneg (non-transgene carrying littermates) and uERβ-OE+. UTI was created by transurethral inoculation of uropathogenic E. coli (UPEC) at a dose of 1 x 10e8 colony forming units (CFU) in 50 µL under anesthesia using established protocol. Urine specimens were collected 1, 2, 3, and 4 days post UPEC inoculation and sampled on agar plates in serial dilution to quantitate bacterial load. After the last urine collection on Day 4, mice were euthanized, and their bladders and kidneys were harvested, homogenized, and plated for bacterial counts. Voiding spot assay (VSA) was performed to compare voiding behavior after UPEC inoculation.

The found that the qPCR showed the ERβ mRNA was significantly elevated in the uERβ-OE+ urothelium. Bladder histology revealed no differences in the 3 cohorts. uERβ-OE+ mice (n=12) cleared urinary UPEC loads significantly more quickly than the 2 control cohorts (n=24) (Figure A, B). Transgenics also had significantly lower bacterial counts measured in bladders and kidneys (Figure C, D) on Day 4. Control animals voided significantly more on Day 1 after UPEC compared to prior to UPEC inoculation. uERβ-OE+ animals had no change in voiding behavior 1 day after UPEC inoculation.

In conclusion they demonstrated that increased ERβ signaling on urothelial cells is protective against both lower and upper urinary tract infections. This uERβ-OE+ mouse model will serve as a valuable tool to identify novel pathways that might be harnessed in UTI treatments which leverage host defense responses activated by ERβ.

Presenter by: Toby Chai MD

Authors: Judy Yeh MD¹, Marian Acevedo MD¹, Lery Alvarez MS¹, Ming Lu MD¹, Warren Hill PhD² 

Author Information: 
1. Yale, New Haven, CT
2. Beth Israel Deaconess, Boston, MA

Written by: Bilal Farhan, MD, Female Urology Fellow and Voiding Dysfunction, Department of Urology, University of California, Irvine at the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction Winter Meeting (SUFU 2018), February 27-March 3, 2018, Austin, Texas