Nicotine, smoking, podocytes, and diabetic nephropathy.

TitleNicotine, smoking, podocytes, and diabetic nephropathy.
Publication TypeJournal Article
Year of Publication2021
AuthorsJaimes EA, Zhou M-S, Siddiqui M, Rezonzew G, Tian R, Seshan SV, Muwonge AN, Wong NJ, Azeloglu EU, Fornoni A, Merscher S, Raij L
JournalAm J Physiol Renal Physiol
Volume320
Issue3
PaginationF442-F453
Date Published2021 03 01
ISSN1522-1466
KeywordsAMP-Activated Protein Kinases, Animals, Apoptosis, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Humans, Mice, Nicotine, Podocytes, Reactive Oxygen Species, Smoking
Abstract

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. 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.

DOI10.1152/ajprenal.00194.2020
Alternate JournalAm J Physiol Renal Physiol
PubMed ID33459165
PubMed Central IDPMC7988804
Grant ListR01 DK118222 / DK / NIDDK NIH HHS / United States
DK083912 / / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) /
DK116101 / / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) /
CA227493 / / HHS | NIH | National Cancer Institute (NCI) /
DK117599 / / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) /
ES014948 / / HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) /
DK100846 / / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) /
DK104753 / / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) /
P30 CA008748 / CA / NCI NIH HHS / United States
CA008748 / / HHS | NIH | National Cancer Institute (NCI) /
Related Faculty: 
Surya V. Seshan, M.D.

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