title: Nicotinic acetylcholine receptor agonists attenuate septic acute kidney injury in mice by suppressing inflammation and proteasome activity.
abstract: Sepsis is one of the leading causes of acute kidney injury (AKI). Septic patients who develop acute kidney injury (AKI) are at increased risk of death. To date there is no effective treatment for AKI or septic AKI. Based on their anti-inflammatory properties, we examined the effects of nicotinic acetylcholine receptor agonists on renal damage using a mouse model of lipopolysaccharide (LPS)-induced AKI where localized LPS promotes inflammation-mediated kidney damage. Administration of nicotine (1 mg/kg) or GTS-21 (4 mg/kg) significantly abrogated renal leukocyte infiltration (by 40%) and attenuated kidney injury. These renoprotective effects were accompanied by reduced systemic and localized kidney inflammation during LPS-induced AKI. Consistent with these observations, nicotinic agonist treatment significantly decreased renal IκBα degradation and NFκB activation during LPS-induced AKI. Treatment of human kidney cells with nicotinic agonists, an NFκB inhibitor (Bay11), or a proteasome inhibitor (MG132) effectively inhibited their inflammatory responses following stimulation with LPS or TNFα. Renal proteasome activity, a major regulator of NFκB-mediated inflammation, was enhanced by approximately 50% during LPS-induced AKI and elevated proteasome activity was significantly blunted by nicotinic agonist administration in vivo. Taken together, our results identify enhanced renal proteasome activity during LPS-induced AKI and the suppression of both proteasome activity and inflammation by nicotinic agonists to attenuate LPS-induced kidney injury.
authors.affiliation: The Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Prodyot K
authors.initials: PK
authors.lastname: Chatterjee
authors.forename: Michael M
authors.initials: MM
authors.lastname: Yeboah
authors.forename: Oonagh
authors.initials: O
authors.lastname: Dowling
authors.forename: Xiangying
authors.initials: X
authors.lastname: Xue
authors.forename: Saul R
authors.initials: SR
authors.lastname: Powell
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D001597:Benzylidene Compounds / Q000008:administration & dosage*; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018733:Nicotinic Antagonists / Q000008:administration & dosage*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D020011:Protective Agents / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D011978:Receptors, Nicotinic / Q000378:metabolism
chemical_list: D001597:Benzylidene Compounds; D008070:Lipopolysaccharides; D018733:Nicotinic Antagonists; D020011:Protective Agents; D011725:Pyridines; D011978:Receptors, Nicotinic; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D046988:Proteasome Endopeptidase Complex