The Effect of Nicotinic Agonist Therapy on Renal Inflammation in Mice with Systemic Lupus Erythematosus

Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease that causes chronic systemic, and specifically renal, inflammation that results in renal injury and hypertension. Under normal conditions, inflammation may be regulated by a neuroimmune reflex referred to as the cholinergic anti-inflammatory pathway; this pathway is mediated by immune cells responding to acetylcholine via the a7-subunit of nicotinic acetylcholine receptors (nAChRs) and when stimulated results in the reduction of tissue-specific inflammation. These a7nAChRs can be activated nonselectively by nicotine and we have previously shown that nicotine attenuates renal inflammation in female SLE mice. However, because nicotine is toxic and addictive, it would not be available to use as a therapy for SLE. We hypothesized that a selective a7nAChR agonist would similarly reduce renal inflammation and protect against the development of renal injury. Methods: In our pilot studies (n=2-3 mice/group), female SLE (NZBWF1) and control (NZW) mice (33 weeks of age) were surgically implanted with osmotic mini-pumps to subcutaneously administer the nicotinic agonist PNU-120596 (3.8 mg/kg/day), or vehicle (100% DMSO) at a rate of 0.25 mL/hour. At 35 weeks, mice were euthanized and tissues harvested. Results: The gene expression of renal cortical tumor necrosis factor (TNF)-a (measured by qRT-PCR using 2-DDCt method normalized to HPRT) was found to be 3-fold higher in SLE mice as compared to control mice. However, PNU-120596 treatment did not have an effect on TNF-a gene expression in SLE or control mice. Renal cortical interferon (IFN)-a gene expression was similar in SLE and control mice. By contrast, PNU-120596 treatment increased IFN-a gene expression in both SLE mice and controls (18-fold and 3-fold, respectively). Conclusions: Although inflammatory markers were increased in SLE mice, as expected, the effect of this PNU-120596 treatment on TNF-a and IFN-a is inconclusive, because statistical analysis was not performed due to the small sample size. Future studies will increase sample size and agonist dosage to further investigate the potential therapeutic effect of nicotinic agonists on SLE-induced inflammation and renal injury.