The cholinergic antiinflammatory 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 which consist of many different subtypes formed by the specific assembly of five polypeptide subunits including 1-10, 1-4, , , and . The alpha7 receptor (7nAChR) mediates the antiinflammatory 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 up-regulated 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, while pretreatment with nicotine downregulated its activation. These results suggest that the 7nAChR plays an important role in the pathophysiology of renal IRI. KEYWORDS: Renal inflammation, cholinergic antiinflammatory pathway, renal injury, STAT3, proteasome activity