Cigarette smoke (CS) is the most important cause of preventable morbidity and mortality in the U.S. Recent clinical studies have suggested that in addition of 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 (MC) are endowed with the nicotinic receptors (nAChRs) 4, 5, 7, 2, 3, 4 and 5. Studies performed in other cell types have shown that these nAChRs are ionotropic receptors that function as agonist-regulated Ca²⁺ 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 cpm vs Nicotine: 2,761 ± 90 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 protein kinase C (PKC) activation, MC synthesize reactive oxygen species (ROS) via NADPH oxidase. In the current studies we demonstrate that PKC inhibition as well as DPI and apocynin, two inhibitors of NADPH oxidase, prevented the effects of nicotine upon MC proliferation and fibronectin production hence establishing ROS as second messengers of nicotine's actions. Furthermore nicotine increased the production of ROS as assessed by DCF-DA fluorescence: Control 184.4 ± 26 arbitrary fluorescence units (AFU) vs. Nicotine 281.5± 26 AFU (N=5, P < 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.