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The α7-nAChR/heme oxygenase-1/carbon monoxide pathway mediates the nicotine counteraction of renal inflammation and vasoconstrictor hyporeactivity in endotoxic male rats

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Abstract

Objective

The objective of the study was to test the hypothesis that nicotine guards against endotoxemia-associated renal inflammation and vasoconstrictor dysfunction via the activation of α7-nicotinic acetylcholine receptors (α7-nAChRs)/heme oxygenase-1 (HO-1) cascade.

Materials

91 male and female rats were included in the study.

Treatments

Lipopolysaccharide (LPS, 5 mg kg−1), nicotine (0.5–2 mg kg−1), pentoxifylline (PTX, TNFα inhibitor, 3 mg kg−1), methyllycaconitine (MLA, α7-nAChR blocker), zinc protoporphyrin (ZnPP, HO-1 inhibitor), hemin (HO-1 inducer), tricarbonyldichlororuthenium (carbon monoxide-releasing molecule, CORM-2) or bilirubin was administered before LPS.

Methods

Isolated perfused kidney was used to evaluate renal vasoconstriction and immunohistochemistry to assess inflammatory cytokines.

Results

LPS reduced renal vasoconstrictions induced by phenylephrine or vasopressin in perfused kidneys of male, but not female, rats. Higher elevations in serum interleukin-1β and renal expressions of inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) were observed in LPS-treated male rats, whereas greater HO-1 expression was evident in endotoxic female rats. LPS effects were reversed by nicotine or PTX. Further, the favorable nicotine actions were (i) diminished by MLA or ZnPP and (ii) replicated by hemin or CORM-2, but not bilirubin, and (iii) associated with exaggerated and MLA-sensitive increases in HO-1 expression.

Conclusions

α7-nAChR/HO-1/CO signaling mediates nicotine protection against renal inflammation and vasoconstrictor hyporeactivity in endotoxic male rats.

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Funding

This study was funded by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895).

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  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

    Abdalla M. Wedn, Sahar M. El-Gowilly & Mahmoud M. El-Mas

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  1. Abdalla M. Wedn
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Correspondence to Mahmoud M. El-Mas.

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Ethics of animal investigations All experimental techniques and animal manipulations carried out in this study were done in accordance with the institutional guidelines on the care and use of laboratory animals and were approved by the Animal Care and Use Committee of the Faculty of Pharmacy, Alexandria University (ACUC project # 28/2014). This article does not contain any studies with human participants performed by any of the authors.

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Wedn, A.M., El-Gowilly, S.M. & El-Mas, M.M. The α7-nAChR/heme oxygenase-1/carbon monoxide pathway mediates the nicotine counteraction of renal inflammation and vasoconstrictor hyporeactivity in endotoxic male rats. Inflamm. Res. 69, 217–231 (2020). https://doi.org/10.1007/s00011-019-01309-w

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