Impairment of AMPK-α2 augments detrusor contractions in bladder ischemia.

Abstract

PURPOSE:

Ischemia disrupts cellular energy homeostasis. Adenosine monophosphate-activated protein kinase alpha-2 (AMPK-α2) is a subunit of AMPK that senses cellular energy deprivation and signals metabolic stress. Our goal was to examine the expression levels and functional role of AMPK-α2 in bladder ischemia.

MATERIALS AND METHODS:

Iliac artery atherosclerosis and bladder ischemia were engendered in apolipoprotein E knockout rats by partial arterial endothelial denudation using a balloon catheter. After eight weeks, total and phosphorylated AMPK-α2 expression was analyzed by western blotting. Structural integrity of AMPK-α2 protein was assessed by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Functional role of AMPK-α2 was examined by treating animals with the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D ribofuranoside (AICAR). Tissue contractility was measured in the organ bath and bladder nerve density was examined by immunostaining.

RESULTS:

Total AMPK-α2 expression increased in bladder ischemia, while phosphorylated AMPK-α2 was significantly downregulated. LC-MS/MS suggested post-translational modification of AMPK-α2 functional domains including phosphorylation sites, suggesting accumulation of catalytically inactive AMPK-α2 in bladder ischemia. Treatment of rats with AICAR diminished the force of overactive detrusor contractions and increased bladder capacity but did not have a significant effect on the frequency of bladder contractions. AICAR diminished contractile reactivity of ischemic tissues in the organ bath and prevented loss of nerve fibers in bladder ischemia.

CONCLUSIONS:

Ischemia induces post-translational modification of AMPK-α2 protein. Impairment of AMPK-α2 may contribute to overactive detrusor contractions and loss of nerve fibers in bladder ischemia. AMPK activators may have therapeutic potential against detrusor overactivity and neurodegeneration in bladder conditions involving ischemia.

• Authors: Jing-Hua Yang, Wanting Niu, Yedan Li, Kazem M Azadzoi
• Journal: Investigative and clinical urology (Investig Clin Urol) Vol. 62 Issue 5 Pg. 600-609 (09 2021) ISSN: 2466-054X [Electronic] Korea (South)
• PMID: 34387036 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Korean Urological Association, 2021.

Chemical References

• Prkaa2 protein, rat
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (physiology)
• Animals
• Ischemia (physiopathology)
• Muscle Contraction
• Rats
• Urinary Bladder (blood supply, physiopathology)