Nrf2 PLAYS A CRUCIAL ROLE IN THE PATHOGENESIS OF ISCHEMIA-INDUCED BLADDER OVERACTIVITY

Funahashi Y1, Majima T1, Matsukawa Y1, Takai S1, Yoamamoto T1, Gotoh M1

Research Type

Basic Science / Translational

Abstract Category

Overactive Bladder

Abstract 463
Basic Science: Overactive Bladder and Pain
Scientific Podium Short Oral Session 24
Thursday 30th August 2018
15:00 - 15:07
Hall C
Animal Study Detrusor Overactivity Physiology
1. Department of Urology, Nagoya University Graduate School of Medicine
Presenter
Y

Yasuhito Funahashi

Links

Abstract

Hypothesis / aims of study
Pelvic ischemia induces bladder overactivity by stimulating the bladder and its afferent nerves. Nuclear factor erythroid 2-related factor 2 (Nrf2) protects cells from oxidative stress; however, its role in the pathogenesis of ischemic bladder overactivity is unknown. This study examined the relationship between Nrf2 expression and bladder overactivity using a pelvic ischemia mouse model.
Study design, materials and methods
C57BL/6 mice and Nrf2 knockout (KO) mice were used in this study. Pelvic ischemia was induced by adding L-NG-nitroarginine methyl ester (L-NAME; 0.3 g/L) to their drinking water. On day 7, the blood flow in the capillaries on the bladder surface was measured using a charge-coupled device camera (ref. 1), cystometrography was performed in the awake condition (infusion speed 0.5 mL/h), and the bladder was excised for histological evaluation and to quantify oxidative stress markers.
Results
Immunohistochemical staining of the bladder showed that Nrf2 was mainly expressed in the urothelium and was translocated from the cytoplasm to the nucleus on administration of L-NAME to the C57BL/6 mice. The bladder microcirculation was altered in the ischemia groups in both the C57BL/6 and Nrf2 KO mice (Fig. 1). Oxidative stress markers in the bladder (malondialdehyde and HIF-1α) increased in the pelvic ischemia mice, and this was more apparent in the Nrf2 KO mice. Cystometrography demonstrated that the intercontraction intervals were shorter in the ischemia groups. Nrf2 KO mice micturated more frequently on induction of pelvic ischemia (Fig. 2).
Interpretation of results
Activation of the Nrf2 signaling pathway, which leads to the upregulation of antioxidative genes, has been reported to protect neurons against neurodegenerative diseases; to promote myocyte differentiation, muscle contractility, and metabolic properties in a diabetic muscle atrophy model; and to protect various cells from apoptosis. This study demonstrated that Nrf2 translocated from the cytoplasm to the nucleus in the pelvic ischemia groups. We interpret this as a response to protect organs from ischemic injury. Although bladder blood flow was altered similarly in both the normal and Nrf2 KO mice, ischemic damage and bladder overactivity were more apparent in the Nrf2 KO mice. These results suggest that Nrf2 plays an important role in the development of ischemia-induced bladder overactivity and could be a therapeutic target for overactive bladder associated with pelvic ischemia.
Concluding message
Pelvic ischemia caused by administering L-NAME to mice induced detrusor overactivity. The ischemic damage and ischemia-induced bladder overactivity were more severe in Nrf2 KO mice.
Figure 1
Figure 2
References
  1. Mizuno H, Yamamoto T, Okutsu H, Ohtake A, Sasamata M, Matsukawa Y, Funahashi Y, Kato M, Hattori R, Gotoh M. Effect of tamsulosin on bladder microcirculation in a rat ischemia-reperfusion model, evaluated by pencil lens charge-coupled device microscopy system. Urology 2010; 76(5): 1266. e1261-1265.
Disclosures
<span class="text-strong">Funding</span> Japanese Grants-in-Aid for Scientific Research <span class="text-strong">Clinical Trial</span> No <span class="text-strong">Subjects</span> Animal <span class="text-strong">Species</span> Mouse <span class="text-strong">Ethics Committee</span> Nagoya University Institutional Animal Care and Use Comittee