title: Nicotine exposure and the progression of chronic kidney disease: role of the α7-nicotinic acetylcholine receptor.
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.
authors.affiliation: Nephrology Division, Department of Medicine, University of Alabama at Birmingham, 1530 3 Ave South, Birmingham, AL 3594-0007, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rezonzew
authors.forename: Phillip
authors.initials: P
authors.lastname: Chumley
authors.forename: Wenguang
authors.initials: W
authors.lastname: Feng
authors.forename: Ping
authors.initials: P
authors.lastname: Hua
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009392:Nephrectomy / Q000009:adverse effects; D009538:Nicotine / Q000009:adverse effects* / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D016212:Transforming Growth Factor beta; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D009538:Nicotine; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D000157:Aconitine