KMID : 1011820210620050600
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Investigative and Clinical Urology 2021 Volume.62 No. 5 p.600 ~ p.609
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Impairment of AMPK-¥á2 augments detrusor contractions in bladder ischemia
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Yang Jing-Hua
Niu Wanting Li Yedan Azadzoi Kazem M.
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Abstract
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Purpose: Ischemia disrupts cellular energy homeostasis. Adenosine monophosphate-activated protein kinase alpha-2 (AMPK-¥á2) 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-¥á2 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-¥á2 expression was analyzed by western blotting. Structural integrity of AMPK-¥á2 protein was assessed by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Functional role of AMPK-¥á2 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-¥á2 expression increased in bladder ischemia, while phosphorylated AMPK-¥á2 was significantly downregulated. LC-MS/MS suggested post-translational modification of AMPK-¥á2 functional domains including phosphorylation sites, suggesting accumulation of catalytically inactive AMPK-¥á2 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-¥á2 protein. Impairment of AMPK-¥á2 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.
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KEYWORD
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Bladder, Ischemia, Metabolic stress, Overactive detrusor, Peripheral arterial disease
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