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Nicotinic acetylcholine receptor expression and regulation in the rat kidney after ischemia-reperfusion injury

¹Laboratory of Medicinal Biochemistry, The Feinstein Institute for Medical Research North Shore-LIJ Health System, Manhasset, ²Elmezzi Graduate School of Molecular Medicine, ³Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset; and ⁴Department of Pathology, North Shore University Hospital, Manhasset, New York

Submitted 16 April 2008 ; accepted in final form 7 July 2008

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 1–10, β1–4, , , and . The 7 receptor (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 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 7nAChR activation. RT-PCR and immunohistochemistry showed constitutive expression of many nAChR subunits. Immunohistochemistry localized basal 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 7nAChR subunit protein after renal I/R injury. Interestingly, pretreatment with nicotine, which improves the outcome after renal I/R injury, reduced the 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 7nAChR plays an important role in the pathophysiology of renal I/R injury.

renal inflammation; cholinergic anti-inflammatory pathway; renal injury; STAT3; proteasome activity

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