title: AMPK potentiates hypertonicity-induced apoptosis by suppressing NFκB/COX-2 in medullary interstitial cells.
abstract: Cells residing in the hypertonic, hypoxic renal medulla depend on dynamic adaptation mechanisms to respond to changes in energy supply and demand. The serine/threonine kinase 5'-AMP protein kinase (AMPK) is a sensor of cellular energy status, but whether it contributes to the survival of cells in the renal medulla is unknown. Here, hypertonic conditions induced a decrease in AMPK phosphorylation within 12 hours in renal medullary interstitial cells (RMIC), followed by a gradual return to baseline levels. Activation of AMPK markedly increased hypertonicity-induced apoptosis of RMICs and suppressed both hypertonicity-induced NFκB nuclear translocation and cyclooxygenase-2 (COX-2) activation; overexpression of COX-2 significantly attenuated these effects. AMPK activation also markedly reduced generation of reactive oxygen species and nuclear expression of tonicity-responsive enhancer-binding protein, which prevented upregulation of osmoprotective genes. In vivo, pharmacologic activation of AMPK led to massive apoptosis of RMICs and renal dysfunction in the setting of water deprivation in mice. Taken together, these results identify a critical role for AMPK in the maintenance of RMIC viability and suggest that AMPK modulates the NFκB-COX-2 survival pathway in the renal medulla. Furthermore, this study raises safety concerns for the development of AMPK activators as anti-diabetic drugs, especially for patients prone to dehydration.
authors: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors: Qifei
authors: Q
authors: Han
authors: Xiaoyan
authors: X
authors: Zhang
authors: Rui
authors: R
authors: Xue
authors: Hang
authors: H
authors: Yang
authors: Yunfeng
authors: Y
authors: Zhou
authors: Xiaomu
authors: X
authors: Kong
authors: Pan
authors: P
authors: Zhao
authors: Jing
authors: J
authors: Li
authors: Jichun
authors: J
authors: Yang
authors: Yi
authors: Y
authors: Zhu
authors: Youfei
authors: Y
authors: Guan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003681:Dehydration / Q000201:enzymology / Q000503:physiopathology; D004789:Enzyme Activation; D011464:Epoprostenol; D015870:Gene Expression; D007679:Kidney Medulla / Q000166:cytology / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009997:Osmotic Pressure; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C492200:Nfat5 protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D011464:Epoprostenol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2; D053148:Caspase 3