1. Nicotine exposure and the progression of chronic kidney disease: role of the α7-nicotinic acetylcholine receptor.
- Author
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Rezonzew G, Chumley P, Feng W, Hua P, Siegal GP, and Jaimes EA
- Subjects
- Aconitine analogs & derivatives, Aconitine pharmacology, Animals, Blood Pressure drug effects, Blood Pressure physiology, Chronic Disease, Disease Models, Animal, Kidney Diseases etiology, Kidney Diseases metabolism, Male, NADPH Oxidase 4, NADPH Oxidases metabolism, Nephrectomy adverse effects, Nicotine pharmacology, Nicotinic Antagonists pharmacology, Oxidative Stress drug effects, Oxidative Stress physiology, Rats, Rats, Sprague-Dawley, Receptors, Nicotinic drug effects, Transforming Growth Factor beta metabolism, alpha7 Nicotinic Acetylcholine Receptor, Disease Progression, Kidney Diseases physiopathology, Nicotine adverse effects, Receptors, Nicotinic physiology
- Abstract
Clinical studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease (CKD). We have shown that nicotine promotes mesangial cell proliferation and hypertrophy via nonneuronal nicotinic acetylcholine receptors (nAChRs). The α7-nAChR is one of the most important subunits of the nAChRs. These studies were designed to test the hypothesis that nicotine worsens renal injury in rats with 5/6 nephrectomy (5/6Nx) and that the α7-nAChR subunit is required for these effects. We studied five different groups: Sham, 5/6Nx, 5/6Nx + nicotine (Nic; 100 μg/ml dry wt), 5/6Nx + Nic + α7-nAChR blocker methyllicaconitine (MLA; 3 mg·kg(-1)·day(-1) sq), and Sham + Nic. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. After 12 wk, the rats were euthanized and kidneys were collected. We observed expression of the α7-nAChR in the proximal and distal tubules. The administration of nicotine induced a small increase in blood pressure and resulted in cotinine levels similar to those found in the plasma of smokers. In 5/6Nx rats, the administration of nicotine significantly increased urinary protein excretion (onefold), worsened the glomerular injury score and increased fibronectin (∼ 50%), NADPH oxidase 4 (NOX4; ∼100%), and transforming growth factor-β expression (∼200%). The administration of nicotine to sham rats increased total proteinuria but not albuminuria, suggesting direct effects on tubular protein reabsorption. These effects were prevented by MLA, demonstrating a critical role for the α7-nAChR as a mediator of the effects of nicotine in the progression of CKD.
- Published
- 2012
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