Abstract P162: Nicotine via Cd36, Cox2 and Oxidative Stress Promotes Podocyte Injury: Link Between E-cigarettes and Renal Disease Progression?
Cigarette smoking (CS) accounts for 175,000 annual CV deaths in US. CKD is a major CV risk factor. Epidemiologically link between CS proteinuria and progression of diabetic and of hypertensive nephropathy is documented. We showed that Nicotine (NIC) in concentrations achieved in CS and E- smokers a)Increased proteinuria (100%) renal Nox4 & Nitrotyrosine in diabetic db/db mice (AJP ‘10) and b) Promoted in human macrophages O2- production and foam cell formation associated with upregulation of B scavenger receptor CD36 and oxLDL uptake (AJP’13). Podocytes (POD) are vulnerable to diabetes and to hypertension; POD injury results in detachment and glomerulosclerosis. We demonstrated in human POD NIC receptors α2, 3,4 and β3 Methods: We treated human POD with NIC, 100nmol/L, a concentration attained in serum of CS and E-Cigarettes smokers, and determined O2- production with lucigening; some POD were pre-incubated with Hexametonium: blocker of NIC receptors; DPI: inhibitor of NADPH; Catalase: inhibitor of H2O2 and AICAR: activator of AMPK, a suppressor of NADPH. By Western Blot (WB) we determined in Control and NIC exposed POD, CD36, COX2 known to induce POD injury (JASN ‘08) and Synaptopodin (Synpo) a stabilizer of POD actin skeleton. In POD incubated with 50ug/ml oxLDL we measured POD apoptosis (APOPT) by flow cytometry. Stat. ANOVA- Bonferonni’s- Scheffe’s. Results: NIC increased POD O2- production 225% (200 to 450 CPM/ug); Synpo expression was reduced 50% (1to 0.5) (p< 0.05). DPI and AICAR prevented Synpo reduction and increase in O2- (p<0.05). NIC upregulated expression of COX2 300% (0.5-1.5) and CD36 40 % (1-1.4) (p<0.05). DPI, Catalase, and Hexametonium inhibited CD36 and COX2 upregulation. The COX inhibitor NS-398 prevented O2-production and CD36 upregulation .POD incubation with oxLDL plus NIC significantly increased POD oxLDL uptake and APOPT 10% over baseline (2%),(p<0.05) both inhibited by CD36-SiRNA. Conclusion: NIC activated in human POD a reciprocal interplay between NADPH oxidases and COX2 that increased O2- production, reduced Synpo and upregulated the B scavenger receptor CD36 that, via increased uptake of oxidized LDL, promoted podocyte apoptosis. We surmise that these novel findings implicate NIC as a risk factor for CVD and CKD progression.
Author Disclosures: L. Raij: None. R. Tian: None. M. Zhou: None.
- © 2015 by American Heart Association, Inc.