Nicotinic acetylcholine receptor agonists attenuate septic acute kidney injury in mice by suppressing inflammation and proteasome activity.

Prodyot K Chatterjee,Oonagh Dowling,Xiangying Xue,Yousef Al-Abed,Christine N Metz,Michael M Yeboah,Saul R Powell,Niels Olsen Saraiva Câmara

doi:10.1371/journal.pone.0035361

Prodyot K Chatterjee, Oonagh Dowling + Show 6 more

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https://doi.org/10.1371/journal.pone.0035361

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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.

Highlights

The kidney is a frequent target for sepsis-associated multi-organ injury, with increasing prevalence of acute kidney injury (AKI) observed among patients with severe sepsis (23%) and septic shock (51%) compared to patients with moderate sepsis (19%) (Reviewed in [1,2])
Both nicotine and GTS-21 treatment reduced leukocyte infiltration (assessed by renal myeloperoxidase (MPO) levels) within the kidney by approximately 40%, during experimental LPS-AKI compared to saline treatment (Fig. 1A)
Septic AKI was accompanied by significant kidney inflammation as measured by kidney TNFa, CCL2, and CXCL10 levels (Figs. 2B–D); renal concentrations of these pro-inflammatory mediators were blunted by treatment with nicotinic agonists (Figs. 2B–D)

Summary

Introduction

The kidney is a frequent target for sepsis-associated multi-organ injury, with increasing prevalence of acute kidney injury (AKI) observed among patients with severe sepsis (23%) and septic shock (51%) compared to patients with moderate sepsis (19%) (Reviewed in [1,2]). Severe sepsis and septic shock are the leading causes of AKI in intensive care patients and may be responsible for more than 50% of cases of AKI in such patients. Epidemiological, clinical, and experimental studies support the concept that pro-inflammatory mediators produced during sepsis promote intrarenal hemodynamic changes, endothelial dysfunction, leukocyte infiltration, and damaging tissue inflammation that lead to renal failure. Despite several years of intense investigations and significant advances in medicine and therapeutics, there are still no effective treatments for septic AKI

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