title: Coenzyme Q10 protects renal proximal tubule cells against nicotine-induced apoptosis through induction of p66shc-dependent antioxidant responses.
abstract: Chronic nicotine exposure (via smoking, E-cigarettes) increases oxidative stress in the kidney that sensitizes it to additional injury in experimental models and in the renal patient. The pro-apoptotic p66shcprotein-via serine36 phosphorylation that facilitates its mitochondrial translocation and therein cytochrome c binding-generates oxidative stress that leads to injury of renal proximal tubule cells during chronic nicotine exposure. Coenzyme Q10-a clinically safe antioxidant-has been used against nicotine/smoke extract-associated oxidative stress in various non-renal cells. This study explored the anti-oxidant/anti-apoptotic effect of Coenzyme Q10 on nicotine-induced oxidative stress and its impact on p66shc in cultured rat renal proximal tubule cells (NRK52E). We studied the anti-oxidant effect of 10 µM Coenzyme Q10 using various mutants of the p66shc gene and also determined the induction of selected anti-oxidant entities (antioxidant response element, promoter of the manganese superoxide dismutase gene) in reporter luciferase assay during oxidative stress induced by 200 µM nicotine. Our studies revealed that Coenzyme Q10 strongly inhibits nicotine-mediated production of reactive oxygen species and consequent apoptosis that requires serine36 phosphorylation but not mitochondrial translocation/cytochrome c binding of p66shc. While both nicotine and Coenzyme Q10 stimulates the p66shc promoter, only nicotine exposure results in mitochondrial translocation of p66shc. In contrast, the Coenzyme Q10-stimulated and non-mitochondrial p66shcactivates the anti-oxidant manganese superoxide dismutase promoter via the antioxidant response elements and hence, rescues cells from nicotine-induced oxidative stress and consequent apoptosis.
authors: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Research Wing Room R116/B, 2500 N. State St., Jackson, MS, 39216, USA. iarany@umc.edu.
authors: Istvan
authors: I
authors: Arany
authors: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Research Wing Room R116/B, 2500 N. State St., Jackson, MS, 39216, USA.
authors: Anthony
authors: A
authors: Carter
authors: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Research Wing Room R116/B, 2500 N. State St., Jackson, MS, 39216, USA.
authors: Samuel
authors: S
authors: Hall
authors: Department of Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Tibor
authors: T
authors: Fulop
authors: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Research Wing Room R116/B, 2500 N. State St., Jackson, MS, 39216, USA.
authors: Mehul
authors: M
authors: Dixit
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045304:Cytochromes c / Q000378:metabolism; D066300:Electronic Nicotine Delivery Systems; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species; D012907:Smoking / Q000009:adverse effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics* / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000235:genetics
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014451:Ubiquinone; D009538:Nicotine; D045304:Cytochromes c; C024989:coenzyme Q10
keywords: Antioxidant; Apoptosis; Coenzyme Q10; Nicotine; Oxidative stress; P66shc; Protection