Nicotine: the link between cigarette smoking and the progression of renal injury?
Cigarette smoke (CS) is the most important source of preventable morbidity and mortality in the United States. Recent clinical studies have suggested that, in addition to being a major cardiovascular risk factor, CS promotes the progression of kidney disease. The mechanisms by which CS promotes the progression of chronic kidney disease have not been elucidated. Here we demonstrate for the first time that human mesangial cells (MCs) are endowed with the nicotinic ACh receptors (nAChRs) alpha4, alpha5, alpha7, beta2, beta3, and beta4. Studies performed in other cell types have shown that these nAChRs are ionotropic receptors that function as agonist-regulated Ca(2+) channels. Nicotine induced MC proliferation in a dose-dependent manner. At 10 (-7) M, a concentration found in the plasma of active smokers, nicotine induced MC proliferation [control, 1,328 +/- 50 vs. nicotine, 2,761 +/- 90 counts/minute (cpm); P < 0.05] and increased the synthesis of fibronectin (50%), a critical matrix component involved in the progression of chronic kidney disease. We and others have shown that, in response to PKC activation, MC synthesize reactive oxygen species (ROS) via NADPH oxidase. In the current studies we demonstrate that PKC inhibition as well as diphenyleneiodonium and apocynin, two inhibitors of NADPH oxidase, prevented the effects of nicotine on MC proliferation and fibronectin production, hence establishing ROS as second messengers of the actions of nicotine. Furthermore, nicotine increased the production of ROS as assessed by 2',7'-dichlorofluorescein diacetate fluorescence [control, 184.4 +/- 26 vs. nicotine, 281.5 +/- 26 arbitrary fluorescence units (AFU); n = 5 experiments, P < 0.05]. These studies unveil previously unrecognized mechanisms that indict nicotine, a component of CS, as an agent that may accelerate and promote the progression of kidney disease.
Jaimes
Edgar A
EA
VA Medical Center, 1201 NW 16th St., Renal Section, Rm. A-1009, Miami, FL 33125, USA. ejaimes@med.miami.edu
Tian
Run-Xia
RX
Raij
Leopoldo
L
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology* / Q000503:physiopathology; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D009538:Nicotine / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects* / Q000503:physiopathology; D013638:Tars / Q000494:pharmacology
D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D013638:Tars; C024746:tobacco tar; D009538:Nicotine