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Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users. NEW & NOTEWORTHY In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy.

Background: Intermittent smoking is prevalent among Hispanics, but little is known about whether this smoking pattern associates with increased chronic kidney disease (CKD) risk in this population. The objective of the present study is to identify patterns of exposure associated with CKD in US Hispanics., Methods: We used cross-sectional data on 15 410 participants of the Hispanics Community Health Study/the Study of Latinos, a population-based study of individuals aged 18-74 years, recruited in 2008 to 2011 from four US field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA). Smoking exposure was obtained through a questionnaire. CKD was defined by an estimated glomerular filtration rate of <60 mL/min/1.73 m(2) or a urine albumin-to-creatinine ratio of ≥30 mg/g., Results: Approximately 14% of individuals were daily and 7% were intermittent smokers, and 16% were past smokers. There was a significant interaction between smoking status and pack-years of exposure (P = 0.0003). In adjusted models, there was an increased odds of CKD among daily, intermittent and past smokers by pack-years compared with never smokers. The association of intermittent smokers was significant at 10 pack-years [odds ratio (OR) = 1.38, 95% confidence intervals (CI) 1.06, 1.81], whereas for daily smokers this association was observed at 40 pack-years (OR = 1.43, 95% CI 1.09, 1.89)., Conclusions: Our findings of increased risk of CKD among Hispanics who are intermittent smokers support screening and smoking cessation interventions targeted to this population for the prevention of CKD. It also suggests novel mechanistic pathways for kidney toxicity that should be further explored in future studies., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)