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.