Simvastatin and tempol protect against endothelial dysfunction and renal injury in a model of obesity and hypertension

Obesity and hypertension are risk factors for the development of chronic kidney disease. The mechanisms by which elevated blood pressure and fatty acids lead to the development of renal injury are incompletely understood. Here, we investigated the contributions of cholesterol and oxidative stress to renal endothelial dysfunction and glomerular injury in a model of obesity and hypertension. Male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were fed a normal diet, a high-fat diet, a high-fat diet with tempol, or a high-fat diet with simvastatin for up to 10 wk. Blood pressure was not altered by a high-fat diet or treatments. After 3 wk, renal afferent dilatory responses to acetylcholine were impaired in WKY rats and SHR fed a high-fat diet. Tempol treatment prevented this vascular dysfunction in both strains; however, simvastatin treatment demonstrated greater beneficial effects in the SHR. Albuminuria was observed in the SHR and was exacerbated by a high-fat diet. Tempol and simvastatin treatment significantly ameliorated albuminuria in the SHR fed a high-fat diet. Ten weeks on a high-fat resulted in an increase in urinary 8-isoprostane in WKY rats and SHR, and tempol and simvastatin treatment prevented this increase, indicating a reduction in renal oxidative stress. Monocyte chemoattractant protein-1 (MCP-1) excretion was significantly elevated by a high-fat diet in both strains, and tempol prevented this increase. Interestingly, simvastatin treatment had no effect on MCP-1 levels. These data indicate that tempol and simvastatin treatment via a reduction in oxidative stress improve renal endothelial function and decrease glomerular injury in a model of obesity and hypertension.

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CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice

Cardiovascular Research ◽

10.1093/cvr/cvx197 ◽

2017 ◽

Vol 114 (2) ◽

pp. 312-323 ◽

Cited By ~ 11

Author(s):

Sebastian Steven ◽

Mobin Dib ◽

Michael Hausding ◽

Fatemeh Kashani ◽

Matthias Oelze ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

High Fat Diet ◽

Immune Cell ◽

Vascular Inflammation ◽

Human Study ◽

Isometric Tension ◽

Wild Type ◽

High Fat ◽

Aorta Ascendens

Abstract Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor (6877002) therapy. In a small human study higher serum sCD40L levels and an inflammatory phenotype were detected in the blood and Aorta ascendens of obese patients (body mass index > 35) that underwent by-pass surgery. Conclusion CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice and potentially humans. Thus, CD40L represents a therapeutic target in lipid metabolic disorders which is a leading cause in cardiovascular disease.

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The Effect of Rice Bran Extract on Arterial Blood Pressure, Hepatic Steatosis, and Inflammation in Mice Fed with a High-Fat Diet

Journal of Nutrition and Metabolism ◽

10.1155/2020/8374287 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Naphatsanan Duansak ◽

Pritsana Piyabhan ◽

Umarat Srisawat ◽

Jarinyaporn Naowaboot ◽

Nusiri Lerdvuthisopon ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Diastolic Blood Pressure ◽

Arterial Blood Pressure ◽

High Fat Diet ◽

High Fat ◽

Protein Levels ◽

Arterial Blood ◽

Cox 2 ◽

And Oxidative Stress

Background. Inflammation and hypertension are primary mechanisms involving in obesity-associated adverse effects of a high-fat diet. The aim of this study was to evaluate the effects of rice bran extract (RBE) on arterial blood pressure, hepatic steatosis, inflammation, and oxidative stress in high-fat diet (HFD)-induced obese mice. Methods. Male ICR mice were divided into four groups, including a normal-diet control group, a high-fat diet (HFD) (60% kcal from fat) group, an HFD group treated with RBE (220 mg/kg/day), and an HFD group treated with 1100 mg/kg/day for eight weeks. Besides body weight and arterial blood pressure, we determined liver values of total cholesterol, triglyceride, as well as percent body fat, tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), nuclear factor kappa-B (NF-κB), matrix metalloprotease-9 (MMP-9), cyclooxygenase-2 (COX-2), and mRNA endothelial nitric oxide synthase (eNOS). Results. The HFD group had increased body weight, increased systolic and diastolic blood pressure, liver total cholesterol, triglyceride, NF-κB, COX-2 and MMP-9 protein levels, and decreased mRNA eNOS in the aorta. Mice of the HFD group receiving RBE had reduced diastolic blood pressure, as well as significantly decreased liver and serum TNF-α and MDA levels in the liver, and reduced NF-κB levels in both the liver and heart. Conclusions. These results demonstrate that RBE decreases diastolic blood pressure, the liver lipid droplet accumulation, liver and myocardial NF-κB, myocardial COX-2 and MMP-9 protein levels, and oxidative stress. Moreover, RBE may improve endothelial function and may alleviate adverse health effects associated with obesity including obesity-associated hypertension.

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Endothelial Dysfunction and the Development of Renal Injury in Spontaneously Hypertensive Rats Fed a High-Fat Diet

Hypertension ◽

10.1161/hypertensionaha.107.099499 ◽

2008 ◽

Vol 51 (2) ◽

pp. 352-359 ◽

Cited By ~ 78

Author(s):

Sarah F. Knight ◽

Jeffrey E. Quigley ◽

Jianghe Yuan ◽

Siddhartha S. Roy ◽

Ahmed Elmarakby ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Renal Injury ◽

High Fat Diet ◽

Spontaneously Hypertensive Rats ◽

High Fat ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

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Dietary calcium regulates the risk renal injury in high fat diet induced obese rats by regulating renal lipid metabolism, oxidative stress and inflammation

Archives of Physiology and Biochemistry ◽

10.1080/13813455.2020.1746812 ◽

2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Sandeep Das ◽

Dipayan Choudhuri

Keyword(s):

Oxidative Stress ◽

Lipid Metabolism ◽

Renal Injury ◽

High Fat Diet ◽

Dietary Calcium ◽

High Fat ◽

Obese Rats

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24 Oxidative stress and endothelial dysfunction in high-fat diet-induced obesity in mice

Heart ◽

10.1136/heartjnl-2011-301156.24 ◽

2011 ◽

Vol 97 (24) ◽

pp. x-e8

Author(s):

J. Du ◽

J-Mei

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity ◽

Obesity In Mice

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Exercise alters cardiovascular and renal pregnancy adaptations in female rats born small on a high-fat diet

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00260.2020 ◽

2020 ◽

Author(s):

Dayana Mahizir ◽

Jessica F. Briffa ◽

Kristina Anevska ◽

Glenn D. Wadley ◽

Karen M. Mortiz ◽

...

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Systolic Blood Pressure ◽

High Fat Diet ◽

Cardiovascular Effects ◽

Late Gestation ◽

Female Rats ◽

High Fat ◽

Exercise Interventions ◽

Wistar Kyoto

Intrauterine growth restriction programs adult cardiorenal disease, which may be exacerbated by pregnancy and obesity. Importantly, exercise has positive cardiovascular effects. This study determined if high-fat-feeding exacerbates the known adverse cardiorenal adaptations to pregnancy in rats born small and whether endurance exercise can prevent these complications. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on embryonic day 18 (E18) in Wistar-Kyoto rats. Female offspring consumed a Chow or High-fat-diet (HFD) from weaning and were randomly allocated an exercise protocol at 16 weeks; Sedentary, Exercised before and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Systolic blood pressure was measured pre-pregnancy and rats were mated at 20 weeks. During pregnancy, systolic blood pressure (E18) and renal function (E19) were assessed. Sedentary HFD Control females had increased estimated glomerular filtration rate (eGFR) compared to Chow. Compared to Control, Sedentary Restricted females had increased eGFR, which was not influenced by HFD. Renal function was not affected by exercise and pre-pregnancy blood pressure was not altered. Restricted Chow-fed dams and dams fed a high-fat-diet had a greater reduction in systolic blood pressure during late gestation, which was only prevented by Exercise. In summary, high-fat fed females born small are at a greater risk of altered cardiorenal adaptations to pregnancy. Although cardiovascular dysfunction was prevented by Exercise, renal dysfunction was not affected by exercise interventions. This study highlights that modifiable risk factors can have beneficial effects in the mother during pregnancy, which may impact fetal growth and development.

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Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE

AJP Renal Physiology ◽

10.1152/ajprenal.00364.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. F875-F884 ◽

Cited By ~ 38

Author(s):

Kazuyoshi Inoue ◽

Komal Sodhi ◽

Nitin Puri ◽

Katherine H. Gotlinger ◽

Jiang Cao ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Endothelial Dysfunction ◽

Renal Injury ◽

Vascular Function ◽

Vascular Endothelial ◽

Sprague Dawley ◽

Sd Rats ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

We have previously reported that adenoviral-mediated delivery of cytochrome P-450 (CYP) 4A2, which catalyzes the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), results in endothelial dysfunction and hypertension in Sprague-Dawley (SD) rats (Wang JS, Singh H, Zhang F, Ishizuka T, Deng H, Kemp R, Wolin MS, Hintze TH, Abraham NG, Nasjletti A, Laniado-Schwartzman M. Circ Res 98: 962–969, 2006). In this study, we targeted the vascular endothelium by using a lentivirus construct expressing CYP4A2 under the control of the endothelium-specific promoter VE-cadherin (VECAD-4A2) and examined the effect of long-term CYP4A2 overexpression on blood pressure and kidney function in SD rats. A bolus injection of VECAD-4A2 increased blood pressure ( P < 0.001) by 26, 36, and 30 mmHg 10, 20, and 30 days postinjection, respectively. Arteries from VECAD-4A2-transduced rats produced increased levels of 20-HETE ( P < 0.01), expressed lower levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p-eNOS) ( P < 0.05), generated higher levels of superoxide anion, and displayed decreased relaxing responsiveness to acetylcholine ( P < 0.05). Proteinuria increased by twofold in VECAD-4A2-transduced rats compared with controls. Treatment of VECAD-4A2-transduced rats with HET0016, an inhibitor of 20-HETE biosynthesis, not only attenuated the increase in blood pressure ( P < 0.05) but also improved vascular function (acetylcholine-induced relaxations) and reduced plasma creatinine and proteinuria. HET0016 treatment decreased oxidative stress and increased the phosphorylated state of key proteins that regulate endothelial function, including eNOS, AKT, and AMPK. Collectively, these findings demonstrate that augmentation of vascular endothelial 20-HETE levels results in hypertension, endothelial dysfunction, and renal injury, which is offset by HET0016 through a reduction in vascular 20-HETE coupled with a lessening of oxidative stress and the amplification of pAKT, pAMPK, and p-eNOS levels leading to normalization of endothelial responses.

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