25 results on '"Jaimes, Edgar A."'
Search Results
2. Nicotine, smoking, podocytes, and diabetic nephropathy.
- Author
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Jaimes, Edgar A., Ming-Sheng Zhou, Siddiqui, Mohammed, Rezonzew, Gabriel, Tian, Runxia, Seshan, Surya V., Muwonge, Alecia N., Wong, Nicholas J., Azeloglu, Evren U., Fornoni, Alessia, Merscher, Sandra, and Raij, Leopoldo
- 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. 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]
- Published
- 2021
- Full Text
- View/download PDF
3. Renal cell carcinoma: new insights and challenges for a clinician scientist
- Author
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Shingarev, Roman, primary and Jaimes, Edgar A., additional
- Published
- 2017
- Full Text
- View/download PDF
4. Renal cell carcinoma: new insights and challenges for a clinician scientist.
- Author
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Shingarev, Roman and Jaimes, Edgar A.
- Abstract
There is a growing recognition of the complex interplay between renal cell cancer (RCC), kidney function, mechanical reduction of nephron mass, and systemic agents targeting the cancer. Earlier detection of RCC and rising life expectancy of cancer survivors places a greater emphasis on preservation of renal function after cancer resection and during systemic therapy. Unique adverse effects associated with RCC drugs not only help reveal cancer pathophysiology but also expand our knowledge of normal cell signaling and metabolism. In this review, we outline our current understanding of RCC biology and treatment, their bidirectional relationship with kidney function, and unmet research needs in this field. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
5. Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling
- Author
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Zhou, Ming-Sheng, primary, Chadipiralla, Kiranmai, additional, Mendez, Armando J., additional, Jaimes, Edgar A., additional, Silverstein, Roy L., additional, Webster, Keith, additional, and Raij, Leopoldo, additional
- Published
- 2013
- Full Text
- View/download PDF
6. Nicotine exposure and the progression of chronic kidney disease: role of the α7-nicotinic acetylcholine receptor
- Author
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Rezonzew, Gabriel, primary, Chumley, Phillip, additional, Feng, Wenguang, additional, Hua, Ping, additional, Siegal, Gene P., additional, and Jaimes, Edgar A., additional
- Published
- 2012
- Full Text
- View/download PDF
7. Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers
- Author
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Hua, Ping, primary, Feng, Wenguang, additional, Ji, Shaonin, additional, Raij, Leopoldo, additional, and Jaimes, Edgar A., additional
- Published
- 2010
- Full Text
- View/download PDF
8. Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin II, and oxidative stress
- Author
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Jaimes, Edgar A., primary, Hua, Ping, additional, Tian, Run-Xia, additional, and Raij, Leopoldo, additional
- Published
- 2010
- Full Text
- View/download PDF
9. Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-β, and fibronectin with concomitant increase in nitric oxide bioavailability
- Author
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Zhou, Ming-Sheng, primary, Schuman, Ivonne Hernandez, additional, Jaimes, Edgar A., additional, and Raij, Leopoldo, additional
- Published
- 2008
- Full Text
- View/download PDF
10. Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells
- Author
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Pearse, Damien D., primary, Tian, Run-Xia, additional, Nigro, Jessica, additional, Iorgulescu, Julian B., additional, Puzis, Leopold, additional, and Jaimes, Edgar A., additional
- Published
- 2008
- Full Text
- View/download PDF
11. Upregulation of cortical COX-2 in salt-sensitive hypertension: role of angiotensin II and reactive oxygen species
- Author
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Jaimes, Edgar A., primary, Zhou, Ming-Sheng, additional, Pearse, Damien D., additional, Puzis, Leopold, additional, and Raij, Leopoldo, additional
- Published
- 2008
- Full Text
- View/download PDF
12. Dissociation between metabolic and vascular insulin resistance in aging
- Author
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Schulman, Ivonne Hernandez, primary, Zhou, Ming-Sheng, additional, Jaimes, Edgar A., additional, and Raij, Leopoldo, additional
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- 2007
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13. Nicotine: the link between cigarette smoking and the progression of renal injury?
- Author
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Jaimes, Edgar A., primary, Tian, Run-Xia, additional, and Raij, Leopoldo, additional
- Published
- 2007
- Full Text
- View/download PDF
14. Nitric oxide production duringVibrio choleraeinfection
- Author
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Janoff, Edward N., primary, Hayakawa, Hiroshi, additional, Taylor, David N., additional, Fasching, Claudine E., additional, Kenner, Julie R., additional, Jaimes, Edgar, additional, and Raij, Leopoldo, additional
- Published
- 1997
- Full Text
- View/download PDF
15. Nicotine exposure and the progression of chronic kidney disease: role of the α7-nicotinic acetylcholine receptor.
- Author
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Rezonzew, Gabriel, Chumley, Phillip, Wenguang Feng, Ping Hua, Siegal, Gene P., and Jaimes, Edgar A.
- Abstract
Clinical studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease (CKD). We have shown that nicotine promotes mesangial cell proliferation and hypertrophy via nonneuronal nicotinic acetylcholine receptors (nAChRs). The α7-nAChR is one of the most important subunits of the nAChRs. These studies were designed to test the hypothesis that nicotine worsens renal injury in rats with 5/6 nephrectomy (5/6Nx) and that the α7-nAChR subunit is required for these effects. We studied five different groups: Sham, 5/6Nx, 5/6Nx + nicotine (Nic, 100 μg/ml dry wt), 5/6Nx + Nic + α7-nAChR blocker methyllicaconitine (MLA; 3 mg∙kg
-1 ∙day-1 sq), and Sham + Nic. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. After 12 wk, the rats were euthanized and kidneys were collected. We observed expression of the α7-nAChR in the proximal and distal tubules. The administration of nicotine induced a small increase in blood pressure and resulted in cotinine levels similar to those found in the plasma of smokers. In 5/6Nx rats, the administration of nicotine significantly increased urinary protein excretion (onefold), worsened the glomerular injury score and increased fibronectin (∼ 50%), NADPH oxidase 4 (NOX4; ∼100%), and transforming growth factor-β expression (∼200%). The administration of nicotine to sham rats increased total proteinuria but not albuminuria, suggesting direct effects on tubular protein reabsorption. These effects were prevented by MLA, demonstrating a critical role for the α7-nAChR as a mediator of the effects of nicotine in the progression of CKD. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
16. The transcription factor ETS-1 regulates angiotensin II-stimulated fibronectin production in mesangial cells.
- Author
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Ping Hua, Wenguang Feng, Rezonzew, Gabriel, Chumley, Phillip, and Jaimes, Edgar A.
- Abstract
Angiotensin II (ANG II) produced as result of activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of chronic kidney disease via its hemodynamic effects on the renal microcirculation as well as by its nonhemodynamic actions including the production of extracellular matrix proteins such as fibronectin, a multifunctional extracellular matrix protein that plays a major role in cell adhesion and migration as well as in the development of glomerulosclerosis. ETS-1 is an important transcription factor essential for normal kidney development and glomerular integrity. We previously showed that ANG II increases ETS-1 expression and is required for fibronectin production in mesangial cells. In these studies, we determined that ANG II induces phosphorylation of ETS-1 via activation of the type 1 ANG II receptor and that Erk1/2 and Akt/PKB phosphorylation are required for these effects. In addition, we characterized the role of ETS-1 on the transcriptional activation of fibronectin production in mesangial cells. We determined that ETS-1 directly activates the fibronectin promoter and by utilizing gel shift assays and chromatin immunoprecipitation assays identified two different ETS-1 binding sites that promote the transcriptional activation of fibronectin in response to ANG II. In addition, we identified the essential role of CREB and its coactivator p300 on the transcriptional activation of fibronectin by ETS-1. These studies unveil novel mechanisms involved in RAS-induced production of the extracellular matrix protein fibronectin in mesangial cells and establish the role of the transcription factor ETS-1 as a direct mediator of these effects. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
17. Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers.
- Author
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Hua, Ping, Feng, Wenguang, Ji, Shaonin, Raij, Leopoldo, and Jaimes, Edgar A.
- Subjects
CIGARETTE smoke ,SMOKING ,KIDNEY diseases ,DIABETIC nephropathies ,BLOOD pressure ,BLOOD sugar - Abstract
Epidemilogical studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. We have previously reported that nicotine promotes mesangial cell proliferation and hypertrophy via activation of nonneuronal nicotinic acetylcholine receptors and that nicotine worsens renal injury in a model of acute glomerulonephritis (Jaimes E, Tian RX, RaJj L. Am J Physiol Heart Circ Physiol 292: H76-H82, 20 Jaimes EA, Tian RX, Joshi M, Raij L. Am J Nephrol 29: 319-326 2009). These studies were designed to test the hypothesis that nicotine worsens renal injury in db/db mice, a well-established model of diabetic nephropathy, and that reactive oxygen species play an important as mediators of these effects. For these studies, nicotine (100 µg/ml) was administered in the drinking water to control and db/db mice for 10 wk. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. At death, kidneys were collected for histology and molecular biology. The administration of nicotine did not result in significant changes in blood pressure or blood glucose and resulted in cotinine levels similar to those found in the plasma of smokers. In diabetic mice, the administration of nicotine significantly increased urinary protein excretion (1-fold), glomerular hypertrophy, and mesangial area (-20%). These changes were accompanied by significant increases in NADPH oxidase 4 (~30%) and increased nitrotyrosine and Akt expression. In vitro, we determined that nicotine has additive effects to high glucose on reactive oxygen species generation and Akt phosphorylation in human mesangial cells. These findings unveil novel mechanisms that may result in the development of novel strategies in the treatment and prevention of diabetic nephropathy in smokers. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
18. Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin II, and oxidative stress.
- Author
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Jaimes, Edgar A., Ping Hua, Run-Xia Tian, and Leopoldo Raij
- Subjects
- *
GLUCOSE , *FATTY acids , *ANGIOTENSIN II , *OXIDATIVE stress , *REACTIVE oxygen species , *NITRIC oxide , *PROSTAGLANDINS - Abstract
Glomerular endothelial cells (GEC) are strategically situated within the capillary loop and adjacent to the glomerular mesangium. GEC serve as targets of metabolic, biochemical, and hemodynamic signals that regulate the glomerular microcirculation. Unequivocally, hyperglycemia, hypertension, and the local renin-angiotensin system partake in the initiation and progression of diabetic nephropathy (DN). Whether free fatty acids (FFA) and reactive oxygen species (ROS) that have been associated with the endothelial dysfunction of diabetic macrovascular disease also contribute to DN is not known. Since endothelial cells from different organs and from different species may display different phenotypes, we employed human GEC to investigate the effect of high glucose (22.5 mmol/l), FFA (800 μmol/I), and angiotensin II (ANG II; 10-7 mol/l) on the genesis of ROS and their effects on endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2), and the synthesis of prostaglandins (PGs). We demonstrated that high glucose but not high FFA increased the expression of a dysfunctional eNOS as well as increased ROS from NADPH oxidase (100%) and likely from uncoupled eNOS. ANG II also induced ROS from NADPH oxidase. High glucose and ANG II upregulated (100%) COX-2 via ROS and significantly increased the synthesis of prostacyclin (PGI2) by 300%. In contrast, FFA did not upregulate COX-2 but increased PGI2 (500%). These novel studies are the first in human GEC that characterize the differential role of FFA, hyperglycemia, and ANG II on the genesis of ROS, COX-2, and PGs and their interplay in the early stages of hyperglcyemia. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
19. Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-β, and fibronectin with concomitant increase in nitric oxide bioavailability.
- Author
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Ming-Sheng Zhou, Hernandez Schuman, Ivonne, Jaimes, Edgar A., and Raij, Leopoldo
- Subjects
STATINS (Cardiovascular agents) ,OXIDATIVE stress ,FIBRONECTINS ,NITRIC oxide ,ANGIOTENSIN II ,MESSENGER RNA - Abstract
Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 ± 8 vs. 150 ± 2 mmHg in normal salt diet (0.5% NaCI), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F
2α -isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-β (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg·kg-1 ·day-1 ) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-β1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 ± 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-β 1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
20. Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells.
- Author
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Pearse, Damien D., Run-xia Tian, Nigro, Jessica, Iorgulescu, Julian B., Puzis, Leopold, and Jaimes, Edgar A.
- Subjects
RENIN-angiotensin system ,KIDNEY diseases ,FIBRONECTINS ,REACTIVE oxygen species ,OXIDASES - Abstract
Maladaptive activation of the renin-angiotensin system (RAS) has been shown to play a critical role in the pathogenesis of chronic kidney disease. Reactive oxygen species (ROS) are critical signals for many of the nonhemodynamic effects of angiotensin II (ANG II). We have demonstrated that ANG II increases mesangial and cortical cyclooxygenase-2 (COX-2) expression and activity via NADPH oxidase-derived ROS. The transcription factor ETS-! (E26 transformation-specific sequence) has been identified as a critical regulator of growth-related responses and inflammation. The present studies were designed to determine: 1) whether ANG II induces ETS-1 expression in vitro in cultured rat mesangial cells and in vivo in rats infused with ANG II; and 2) whether ROS and COX-2 are mediators of ETS-l induction in response to ANG II. Mesangial cells stimulated with ANG II (l0
-7 M) exhibited a significant increase in ETS-l expression that was prevented by the angiotensin type 1 receptor blocker candesartan. NADPH oxidase inhibition with dyphenilene iodinium or apocynin also prevented ETS-l induction, establishing the role of ROS as mediators of ETS-1 expression in response to ANG H. COX-2 inhibition prevented ETS-1 expression in response to ANG II, suggesting that COX-2 is required for ETS-1 induction. By utilizing short interfering RNAs against ETS-l, we have also determined that ETS-l is required to induce the production of fibronectin in response to ANG II. Furthermore~ rats infused with ANG LI manifested increased glomerular expression of ETS-!. These studies unveil novel pathways that may play an important role in the pathogenesis of renal injury when RAS is activated. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
21. Upregulation of cortical COX-2 in salt-sensitive hypertension: role of angiotensin II and reactive oxygen species.
- Author
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Jaimes, Edgar A., Ming-Sheng Zhou, Pearse, Damien D., Puzis, Leopold, and Raij, Leopoldo
- Subjects
- *
CYCLOOXYGENASE 2 , *HYPERTENSION , *ANGIOTENSIN II , *REACTIVE oxygen species , *NITRIC oxide , *BIOAVAILABILITY - Abstract
Jaimes EA, Zhou MS, Pearse DD, Puzis L, Raij L. Upregulation of cortical COX-2 in salt-sensitive hypertension: role of angiotensin II and reactive oxygen species. Am J Physiol Renal Physiol 294: F385-F392, 2008. First published December 19, 2007; doi: 10.1152/ajprenal.00302.2007.—Salt-sensitive (SS) hypertension is a vascular diathesis characterized by reduced cardiovascular and renal nitric oxide bioavailability and local upregulation of ANG II. We have demonstrated that rats infused with ANG II manifest increased cortical cyclooxygenase (COX)-2 expression and activity via NADPH oxidase-derived reactive oxygen species (ROS). In the present studies we used Dahl salt-sensitive (DS) rats to test the hypothesis that hypertensive SS rats have increased cortical COX-2 upregulation, which is mediated by ANG II and ROS. DS rats were placed on either a normal-salt diet (0.5% NaCl) or a high-salt diet (4% NaCI) for 6 wk and treated with either the ANG II type 1 (AT1) receptor blocker candesartan (Can, 10 mg·kg-1·day-1) or the SOD mimetic tempol (1 mmol/l). Hypertensive SS rats had a twofold increase in the cortical expression of COX-2 as assessed by Western blot. These changes in COX-2 expression were accompanied by a 10-fold increase in COX-2 mRNA expression and a 2-fold increase in the urinary excretion of PGE2. Treatment with either the AT1 receptor blocker Can or the SOD mimetic tempol did not reduce blood pressure but resulted in significant reductions in the cortical expression of COX-2 and the urinary excretion of PGE2. In conclusion, we have demonstrated that local activation of the renin-angiotensin system, via increased ROS generation, mediates COX-2 upregulation in hypertensive SS rats. These studies unveil novel mechanistic pathways that may play a role in the pathogenesis of hypertensive renal injury. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
22. Hydrogen peroxide downregulates IL-1-driven mesangial iNOS activity: implications for glomerulonephritis.
- Author
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JAIMES, EDGAR A., NATH, KARL A., and RAIJ, LEOPOLDO
- Abstract
In glomerulonephritides, autacoids such as nitric oxide (NO), reactive oxygen species, and prostanoids are produced in increased amounts in response to cytokines such as interleukin-1 (IL-1). These autacoids influence the expression of glomerular injury by their direct as well as interactive actions. We studied the effect of hydrogen peroxide (H2O2) on NO production in rat mesangial cells. We demonstrate that transient exposure of mesangial cells to H2O2 prior to sustained exposure to IL-1 decreased extracellular accumulation of NO2/NO3 and cellular guanosine 3',5'-cyclic monophosphate (cGMP) content. H2O2 markedly impaired inducible nitric oxide synthase (iNOS) activity induced by IL-1 directly measured by the conversion of L-[14C]arginine to L-[14C]citrulline. Such impairment in iNOS activity was accompanied by a parallel reduction in iNOS protein abundance but not by a reduced expression of iNOS mRNA. The inhibitory effect of H2O2 on NOS activity was further supported by peroxide-induced impairment in IL-l-driven, NO-dependent synthesis of prostaglandin E2. Our studies thus provide the first direct evidence of a posttranscriptional inhibitory effect of H2O2 on iNOS activity. Additionally, our studies uncover the existence of a previously unrecognized effect of H2O2 on the production of NO that may exert influence on the severity of glomerular injury during glomerular inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 1997
- Full Text
- View/download PDF
23. Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling.
- Author
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Zhou MS, Chadipiralla K, Mendez AJ, Jaimes EA, Silverstein RL, Webster K, and Raij L
- Subjects
- Animals, Antioxidants pharmacology, Apolipoproteins E genetics, Apolipoproteins E metabolism, Atherosclerosis genetics, Atherosclerosis immunology, Atherosclerosis metabolism, Atherosclerosis pathology, Atherosclerosis prevention & control, CD36 Antigens deficiency, CD36 Antigens genetics, Cell Line, Chemokine CCL2 metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Foam Cells drug effects, Foam Cells metabolism, Humans, Inflammation Mediators metabolism, Interleukin-6 metabolism, Lipopolysaccharide Receptors metabolism, Macrophages immunology, Macrophages metabolism, Mice, Mice, Knockout, PPAR gamma antagonists & inhibitors, PPAR gamma metabolism, Plaque, Atherosclerotic, Protein Kinase C-delta antagonists & inhibitors, Protein Kinase C-delta metabolism, Protein Kinase Inhibitors pharmacology, RNA Interference, Reactive Oxygen Species metabolism, Time Factors, Transfection, Tumor Necrosis Factor-alpha metabolism, Up-Regulation, Atherosclerosis chemically induced, CD36 Antigens metabolism, Lipoproteins, LDL metabolism, Macrophages drug effects, Nicotine toxicity, Signal Transduction drug effects
- Abstract
Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36(+)/CD14(+) cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKCδ phosphorylation, and peroxisome proliferator-activated receptor-γ (PPARγ) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKCδ and PPARγ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-α, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 μg/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE-/- mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36-/- apoE-/- mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use of high concentrations of nicotine independent of their mode of administration.
- Published
- 2013
- Full Text
- View/download PDF
24. The transcription factor ETS-1 regulates angiotensin II-stimulated fibronectin production in mesangial cells.
- Author
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Hua P, Feng W, Rezonzew G, Chumley P, and Jaimes EA
- Subjects
- Animals, Blotting, Western, Cell Line, Cell Nucleus metabolism, Chromatin Immunoprecipitation, Cyclic AMP Response Element-Binding Protein physiology, E1A-Associated p300 Protein physiology, Electrophoretic Mobility Shift Assay, Extracellular Matrix metabolism, Extracellular Signal-Regulated MAP Kinases physiology, Genes, Reporter genetics, Glomerular Mesangium cytology, Glomerular Mesangium drug effects, Immunoprecipitation, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation, Plasmids genetics, Proto-Oncogene Protein c-ets-1 genetics, Rats, Stimulation, Chemical, Transcription, Genetic, Transfection, Angiotensin II pharmacology, Fibronectins biosynthesis, Glomerular Mesangium metabolism, Proto-Oncogene Protein c-ets-1 physiology
- Abstract
Angiotensin II (ANG II) produced as result of activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of chronic kidney disease via its hemodynamic effects on the renal microcirculation as well as by its nonhemodynamic actions including the production of extracellular matrix proteins such as fibronectin, a multifunctional extracellular matrix protein that plays a major role in cell adhesion and migration as well as in the development of glomerulosclerosis. ETS-1 is an important transcription factor essential for normal kidney development and glomerular integrity. We previously showed that ANG II increases ETS-1 expression and is required for fibronectin production in mesangial cells. In these studies, we determined that ANG II induces phosphorylation of ETS-1 via activation of the type 1 ANG II receptor and that Erk1/2 and Akt/PKB phosphorylation are required for these effects. In addition, we characterized the role of ETS-1 on the transcriptional activation of fibronectin production in mesangial cells. We determined that ETS-1 directly activates the fibronectin promoter and by utilizing gel shift assays and chromatin immunoprecipitation assays identified two different ETS-1 binding sites that promote the transcriptional activation of fibronectin in response to ANG II. In addition, we identified the essential role of CREB and its coactivator p300 on the transcriptional activation of fibronectin by ETS-1. These studies unveil novel mechanisms involved in RAS-induced production of the extracellular matrix protein fibronectin in mesangial cells and establish the role of the transcription factor ETS-1 as a direct mediator of these effects.
- Published
- 2012
- Full Text
- View/download PDF
25. Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-beta, and fibronectin with concomitant increase in nitric oxide bioavailability.
- Author
-
Zhou MS, Schuman IH, Jaimes EA, and Raij L
- Subjects
- Animals, Atorvastatin, Biological Availability, Blood Pressure drug effects, Chemokine CCL2 metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Kidney drug effects, Kidney pathology, NADPH Oxidases metabolism, Nitric Oxide Synthase Type II metabolism, Nitric Oxide Synthase Type III, Proteinuria urine, RNA, Messenger metabolism, Rats, Rats, Inbred Dahl, Scavenger Receptors, Class E metabolism, Fibronectins metabolism, Heptanoic Acids pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Kidney physiology, Kidney Failure, Chronic prevention & control, Nitric Oxide physiology, Oxidative Stress drug effects, Pyrroles pharmacology, Transforming Growth Factor beta metabolism
- Abstract
Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 +/- 8 vs. 150 +/- 2 mmHg in normal salt diet (0.5% NaCl), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F(2alpha)-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-beta (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg.kg(-1).day(-1)) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-beta1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 +/- 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-beta1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system.
- Published
- 2008
- Full Text
- View/download PDF
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