title: Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes.
abstract: Diabetes increases the risk and worsens the progression of cognitive decline. Diabetic rats treated with the dual endothelin receptor antagonist bosentan, have been shown to improve hippocampal-based cognitive deficits. The NLRP3 inflammasome has been implicated in vascular complications of diabetes. We hypothesized that diabetes-mediated increase in endothelin-1 (ET-1) in hippocampal cells causes NLRP3 activation and inflammation. An in vitro model was employed by exposing HT22 hippocampal cells to normal (25mM), low (5.5mM) and high (50mM) glucose conditions with and without palmitate (200μM) in the presence and absence of 10μM bosentan for 24h. NLRP3 activity was measured by western blotting for cryopyrin and caspase-1. ET-1 and IL-1β expression was determined by ELISA. HT22 cells synthesize high levels of ET-1 in normal conditions, which was reduced with palmitate and bosentan as well as low and high glucose conditions. Decreased ET-1 levels were associated with greater activation of NLRP3 and IL-1β in normal glucose. High glucose increased NLRP3 markers and activation compared to normal and low glucose. These data suggest that ET-1 may be protective to neurons. Although endothelin antagonism may be beneficial in improving vascular dysfunction and cognitive impairment, its impact on hippocampal neurons should be further explored.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Augusta University, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ward
authors.affiliation: Department of Physiology, Augusta University, United States; Charlie Norwood Veterans Administration Medical Center, Augusta, GA, United States. Electronic address: aergul@gru.edu.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: Diabetes; Endothelin; Hippocampus; NLRP3 inflammasome