Search

Purpose Alpha-melanocyte stimulating hormone ([alpha]-MSH) is known to have anti-inflammatory effects. However, the anti-inflammatory properties of [alpha]-MSH on normal bronchial epithelial cells are largely unknown, especially in the context of in vitro sarcoidosis models. Methods We evaluated the anti-inflammatory effects of [alpha]-MSH on two different in vitro sarcoidosis models (lung-on-membrane model; LOMM and three-dimensional biochip pulmonary sarcoidosis model; 3D-BSGM) generated from NBECs and an in vivo sarcoidosis mouse model. Results Treatment with [alpha]-MSH decreased inflammatory cytokine levels and downregulated type I interferon pathway genes and related proteins in LOMM and 3D-BSGM models. Treatment with [alpha]-MSH also significantly decreased macrophages and cytotoxic T-cells counts in a sarcoidosis mice model. Conclusion Our results confirm the direct role of type I IFNs in the pathogenesis of sarcoid lung granulomas and highlight [alpha]-MSH as a potential novel therapeutic agent for treating pulmonary sarcoidosis. Graphical Abstract, Author(s): Abdolrazagh Hashemi Shahraki [sup.1], Runxia Tian [sup.2], Chongxu Zhang [sup.2], Nevis L. Fregien [sup.2], Pablo Bejarano [sup.3], Mehdi Mirsaeidi [sup.1] Author Affiliations: (1) grid.15276.37, 0000 0004 1936 8091, Division [...]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND Current treatment for the secondary prevention of cardiovascular diseases frequently involves the prescription of several combination therapies, particularly antihypertensive medications and HMG-CoA reductase inhibitor. We have previously shown that in salt-sensitive hypertension either a statin or the calcium channel blocker amlodipine (Aml) have vasoprotective effects. Here, we investigated in aortas from Dahl salt-sensitive (DS) rats the effects of Aml, the statin atorvastatin (AT), and their combination on endothelial function, superoxide (O2−) production, and the expression of endothelial nitric oxide synthase (eNOS), chemokine monocyte chemoattractant protein-1 (MCP-1), and lectin-like oxidized LDL receptor-1 (LOX-1). METHODS Groups of DS rats were fed either normal-salt (NS, 0.5% NaCl) or high-salt (HS, 4% NaCl) diet or a HS diet with AT (15mg/kg/day), Aml (5mg/kg/day) or combination of AT/Aml for 6 weeks. RESULTS Rats on the HS diet developed hypertension, aortic hypertrophy, accompanied by increased plasma C-reactive protein (CRP), aortic O2−, MCP-1 (80%), and LOX-1 (55%) expression and reduced eNOS and endothelial-dependent relaxation to acetylcholine (EDR). Aml reduced systolic blood pressure (SBP), aortic hypertrophy, plasma CRP, vascular O2−, and MCP-1 expression and improved eNOS and EDR. AT reduced aortic hypertrophy and plasma CRP, improved EDR, and normalized vascular O2−, eNOS, and proinflammatory gene expression with mild reduction in SBP. Combination therapy further reduced the SBP and normalized aortic hypertrophy, EDR, and plasma CRP. CONCLUSIONS The combination therapy of Aml/AT has an additive beneficial effect on the vasculature. These novel findings may provide scientific basis for the combination therapy of statins with antihypertensive agents to reduce and prevent cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Epidemiological studies have shown that obesity and cigarette smoking (CS) are major cardiovascular (CV) risk factors and when coexisting in the same individuals have additive/synergistic effects upon CVD development. We have shown that stable compounds of CS (ATVB 2004) as well as nicotine, in concentrations found in smoker’s plasma, promote atherosclerotic CVD (AJP 2013). Here we studied in Sprague Dawley (SD) rats with diet -induced obesity the mechanisms involved in nicotine enhancement of CVD. SD rats (N=6-7 each group) were fed either a high fat (HF) or a standard chow (SCH) diet with or without nicotine (100 mg/kg/day in the drinking water) for 20 weeks. The HF rats developed central obesity, characterized by increased body weight gain (22%) and abdominal fat weight (53%), increased plasma levels of cholesterol (33%), non-esterified free fatty acids (68%), insulin (15%) glucose (12%)and systolic blood pressure (SBP: 146 ± 5 vs. 131 ± 5 mmHg SCH rats, p<0.05). Nicotine further increased SBP in obese HF rats (158 ± 4 mmHg, p<0.05) but not in lean SCH rats. Nicotine significantly increased O2- production in both obese (1689 ± 87 count/min/mg) and lean rats (1074 ± 105 count/min/mg) and further impaired EDR (Emax: 74 ± 5%) in obese HF rats. Nicotine also increased the expression of the macrophage marker ED1 in the aortas of obese HF rats. In peritoneal macrophages from obese HF rats TNFα, IL1β and CD36 were increased, and were further significantly increased in nicotine-treated obese HF rats. Using PCR array for inflammatory cytokines and receptor signaling pathway we found that the aortas from obese HF rats showed 2-4 fold increases in expression of several chemokines and interleukin genes expression; nicotine further increased the expression of 11 pro-inflammatory genes in the aortas from obese HF rats. Our results suggest that nicotine dramatically aggravates the CV effects of diet -induced obesity by increasing oxidative stress, vascular inflammation and endothelial dysfunction. Clinically chronic inhalation of nicotine, as that delivered by E-cigarettes, by individuals unable to quit the habit may have an important pro-atherogenic effect, particularly in obese subjects. [ABSTRACT FROM AUTHOR]

Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap -/- model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrial-dependent superoxide anion (O 2 - ) that promotes endothelin-1 synthesis. Plg via O 2 - also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a "second hit" in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention.