Modulation of the hypoxic response following partial bladder outlet obstruction.

Abstract

PURPOSE:

Tissue level hypoxia has been noted in animal models of partial bladder outlet obstruction. The key mechanisms linking hypoxia and obstruction induced bladder dysfunction remain unknown. 2-Methoxyestradiol is a natural derivative of 17β-estradiol and is currently used as an oncologic agent for its ability to regulate the hypoxia pathway. We investigated the ability of 2-methoxyestradiol to modulate the hypoxia response in a mouse model of bladder obstruction.

MATERIALS AND METHODS:

A group of 5 to 6-week-old female C57BL/6 mice underwent oophorectomy and partial bladder outlet obstruction. Obstructed animals received a subcutaneous pellet of cholesterol placebo (7) or 2-methoxyestradiol plus cholesterol (7). Age matched controls underwent oophorectomy only (8). After 4 weeks the bladders of mice with partial bladder outlet obstruction and of unobstructed animals were harvested. Bladder sections (5 μm) were immunostained for Hypoxyprobe™-1, glucose transporter 1 and hypoxia inducible factor-1α. Real-time polymerase chain reaction was performed for hypoxia inducible factor-1α and lysyl oxidase. Statistical analysis was performed using 1-way ANOVA and the Wilcoxon rank sum test.

RESULTS:

Immunostaining for glucose transporter 1 and Hypoxyprobe-1 revealed the presence of tissue hypoxia after partial bladder outlet obstruction. Immunostaining and real-time polymerase chain reaction demonstrated the up-regulation of hypoxia inducible factor-1α in mice after partial bladder outlet obstruction compared to controls (p = 0.0394). Although not statistically significant, a trend toward lower gene expression of hypoxia inducible factor-1α was seen in mice receiving 2-methoxyestradiol compared to placebo (p = 0.0625). Compared to placebo, 2-methoxyestradiol treatment increased lysyl oxidase expression (p = 0.007).

CONCLUSIONS:

Murine partial bladder outlet obstruction resulted in hypoxia and up-regulation of the hypoxia inducible factor-1 pathway. Subcutaneous 2-methoxyestradiol administration attenuated this response and may be a viable tool to study the role of hypoxia after partial bladder outlet obstruction.

• Authors: Beth A Drzewiecki, Govindaraj Anumanthan, Heidi A Penn, Stacy T Tanaka, John C Thomas, Mark C Adams, John W Brock 3rd, John C Pope 4th, Robert J Matusik, Simon Hayward, Douglass B Clayton
• Journal: The Journal of urology (J Urol) Vol. 188 Issue 4 Suppl Pg. 1549-54 (Oct 2012) ISSN: 1527-3792 [Electronic] United States
• PMID: 22910264 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Estradiol
• 2-Methoxyestradiol

Topics

• 2-Methoxyestradiol
• Animals
• Cell Hypoxia (drug effects)
• Estradiol (analogs & derivatives, pharmacology)
• Female
• Mice
• Mice, Inbred C57BL
• Urinary Bladder Neck Obstruction (metabolism)