Deletion of Nrf2 induced severe oxidative stress and apoptosis in mice model of diabetic bladder dysfunction

Area of Science:

• Biomedical Science
• Molecular Biology
• Endocrinology

Background:

• The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a known therapeutic target for type 2 diabetes mellitus (T2DM).
• The role of Nrf2 in diabetic bladder dysfunction (DBD) remains largely unexplored.
• Understanding Nrf2's impact is crucial for developing targeted therapies for T2DM complications.

Purpose of the Study:

• To investigate the role of Nrf2 in the pathogenesis of diabetic bladder dysfunction.
• To establish and characterize a mouse model of Nrf2 deletion in diabetic bladder dysfunction.
• To elucidate the molecular mechanisms underlying Nrf2's influence on DBD.

Main Methods:

• Generation of a Nrf2 knockout diabetic mouse model using high-fat diet and streptozotocin (STZ).
• Assessment of pathophysiological indexes and bladder morphology.
• Biochemical assays (ELISA) for oxidative stress markers (AGEs, ROS, MDA, SOD, GSH).
• Western blot analysis for NQO1, HO-1, and apoptosis markers (Caspase3, Bax/Bcl-2 ratio).
• Measurement of neurotrophic factor (NGF) levels.

Main Results:

• Nrf2 deletion in diabetic mice (KO-T2DM) exhibited typical DBD pathological features.
• KO-T2DM mice showed elevated levels of AGEs, ROS, and MDA, with decreased SOD and GSH compared to controls.
• Bladder tissues in KO-T2DM mice displayed reduced NQO1 and HO-1 expression, increased apoptosis, and significantly lower NGF levels.
• Compared to wild-type diabetic mice (WT-T2DM), Nrf2 deletion worsened oxidative stress and apoptosis.

Conclusions:

• Nrf2 deletion significantly exacerbates diabetic bladder dysfunction by promoting oxidative stress and apoptosis.
• The study provides the first experimental evidence in a mouse model supporting Nrf2 as a promising therapeutic target for DBD.
• Targeting the Nrf2 pathway may offer a novel strategy for managing diabetic bladder complications.