期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 295, 期 3, 页码 F654-F661出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.90255.2008
关键词
renal inflammation; cholinergic anti-inflammatory pathway; renal injury; STAT3; proteasome activity
资金
- National Institute of General Medical Sciences [R01 GM070727]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM070727] Funding Source: NIH RePORTER
The cholinergic anti-inflammatory pathway is a mechanism whereby local inflammation is modulated by the brain via the vagus nerve and nicotinic acetylcholine receptors (nAChRs). The nAChR family are ligand-gated ion channels that consist of many different subtypes formed by the specific assembly of five polypeptide subunits including alpha 1-10, beta 1-4, gamma, delta, and epsilon. The alpha 7 receptor (alpha 7nAChR) mediates the anti-inflammatory effects of cholinergic stimulation. We recently demonstrated that cholinergic agonists attenuate renal ischemia-reperfusion (I/R) injury in rats. We also showed that tubular epithelial cells express functional nAChRs in vitro. The current studies report the expression, localization, and regulation of the alpha 7nAChR in the rat kidney after I/R injury. We also examined, in this model, potential interactions between cholinergic stimulation and the STAT3 pathway, a key signaling cascade that has been linked to alpha 7nAChR activation. RT-PCR and immunohistochemistry showed constitutive expression of many nAChR subunits. Immunohistochemistry localized basal alpha 7nAChR expression to the endothelium of cortical peritubular capillaries, and its distribution was upregulated after I/R injury. Western blotting also showed an increase in alpha 7nAChR subunit protein after renal I/R injury. Interestingly, pretreatment with nicotine, which improves the outcome after renal I/R injury, reduced the alpha 7nAChR protein after I/R injury. Finally, we found that I/R injury stimulated the STAT3 pathway, whereas pretreatment with nicotine downregulated its activation. These results suggest that the alpha 7nAChR plays an important role in the pathophysiology of renal I/R injury.
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