scholarly journals Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes

2021 ◽  
Vol 23 (1) ◽  
pp. 221
Author(s):  
Vanesa Palau ◽  
Josué Jarrín ◽  
Sofia Villanueva ◽  
David Benito ◽  
Eva Márquez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mouse Model ◽  
High Fat Diet ◽  
Macrophage Infiltration ◽  
Creatinine Ratio ◽  
Wild Type ◽  
High Fat ◽  
Tnf Α ◽  
Galectin 3 ◽  
Factor Α

Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.

scholarly journals Chlorogenic Acid and Geniposide Combination Prevents NASH in Rats Fed High-fat diet via Microbiota and TLR4-LPS Pathway

2021 ◽  
Author(s):  
Zhijia Zhou ◽  
Lingxia Xu ◽  
Shaoliang Zhang ◽  
Shilin Xu ◽  
Yanmiao Yang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Chlorogenic Acid ◽  
Inflammatory Cytokines ◽  
High Fat Diet ◽  
Oral Treatment ◽  
Variable Region ◽  
High Fat ◽  
Tnf Α ◽  
Abundance And Diversity ◽  
Factor Α

Abstract Objective: Chlorogenic acid and geniposide (CG) are derived from traditional Chinese medicine, Yinchenhao Recipe (QCHR), and can improve the clinical efficacy of NASH patients. This study investigated the effects of CG on NASH and expounded its Potential mechanism of action through the LPS-TLR4 pathway and microbiota. Methods: Rats were randomized into Control (C), Model (M), Chlorogenic Acid and Geniposide (CG), Pioglitazone (PH) and Bifico (B) groups. After an 8-week high-fat diet (HFD), CG, PH and B oral treatment were initiated and carried out for a further 8 weeks. The stool samples were used in a16S rDNA V4 highly variable region measurement method in order to regulate the role of CG in gut microbiota. The concentrations of triglyceride (TG), cholesterol (CHO), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) in LPS were detected by the corresponding methods. Results: Observations were made that CG significantly improved the pathology of the liver and terminal ileum tissue. The accumulation of TG and the content of inflammatory cytokines in the liver were significantly decreased and the abundance of Proteobacteria was significantly down-regulated. The expression of TLR4, AP-1, MyD88, and phosphorylated NF-κB p65 were significantly decreased. All the findings above indicated that CG was highly effective in improving the composition of gut microbiota, decreasing the production of endogenous LPS, and reducing the secretion of inflammatory cytokines through the gut-liver axis.Conclusion: CG can regulate the abundance and diversity of the intestinal microbial community and improve liver inflammation and steatosis in NASH rats by reducing LPS-TLR4-mediated inflammation.

scholarly journals Renal microvascular damaged in diabetes mellitus with hyperlipidemia through the regulation of MAMs by PACS2 in endothelial cell

2021 ◽  
Author(s):  
Zhihao Shu ◽  
Shuhua Chen ◽  
Hong Xiang ◽  
Ruoru Wu ◽  
Shaoli Zhao ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Fatty Acid ◽  
Endothelial Cell ◽  
Mouse Model ◽  
Vascular Permeability ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Kidney Tissue ◽  
High Fat

Abstract Background: The prevalence of diabetic vascular complications is rapidly increasing, especially in the diabetes mellitus with hyperlipidemia. Consistent hyperglycemia and hyperlipidemia impairs microvascular, but lack of effective intervention target to prevention or reduced the risk of serious bad ending. Methods: A mouse model of diabetes combined with hyperlipidemia were established by STZ injection and high fat diet to observe the possible damage of HGHF to renal blood vessels include vascular permeability, fibrosis and subcellular structure. Then, we replicated an in vitro endothelial cell injury model treated by 30mm Glucose and 0.1mm palmitic acid to verify its main functional changes. Proteomics and metabolomics were used to explore the molecular mechanisms behind diabetic microvascular damage. The mechanisms were further verified at siRNA interference and transgenic knockout mice. Results: We found that renal vascular permeability impaired and fibrosis increased significantly in the stz+HFD mice. In human umbilical vein endothelial cells (HUVECs) treated with high glucose/high fat (HGHF), the number of mitochondrial-associated membranes (MAMs) and the expression of phosphofurin acidic cluster sorting protein 2 (PACS2) increased. In particular, gene manipulation of PACS2 altered endothelial cell MAMs. Knocking down PACS2 restored the barrier function of HUVECs. In vivo, knocking out PACS2 ameliorated the kidney injury in diabetic mice induced by streptozotocin and fed with high-fat diet for up to 20 weeks. PACS2-/- mice leaked less vascular Evan’s blue and improved glomerular fibrosis in the kidney tissue of hyperglycemia and hyperlipidemia mouse model. We further observed the reduction of fatty acid β-oxidation (FAO), CPT1α expression, and NADPH production in endothelial cells induced by HGHF. These changes in fatty acid metabolism were rescued by silencing PACS2, but were blocked by the FAO inhibitor, etomoxir. Conclusion: PACS2 impacts the metabolic response of endothelial cells to HGHF through MAMs. Loss of PACS2 expression reduces glomerular endothelial cells barrier injury, induced by VE-Cadherin internalized under HGHF. PACS2 play a metabolism and MAMs regulators in the vascular endothelial cells of diabetes with hyperlipidemia.

scholarly journals Mineralocorticoid and Estrogen Receptors in Endothelial Cells Coordinately Regulate Microvascular Function in Obese Female Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Lauren A. Biwer ◽  
Brigett V. Carvajal ◽  
Qing Lu ◽  
Joshua J. Man ◽  
Iris Z. Jaffe
Keyword(s):  
Endothelial Cells ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Microvascular Dysfunction ◽  
Estrogen Receptor Α ◽  
No Synthase ◽  
Wild Type ◽  
High Fat ◽  
Obese Female

Obesity impairs endothelial-mediated vasodilation, the earliest step in vascular disease and a contributor to hypertension. We previously demonstrated that endothelial cell MR (mineralocorticoid receptor) deletion prevents obesity-induced microvascular dysfunction in females by increasing nitric oxide (NO)-mediated vasodilation. ERα (Estrogen receptor α) can oppose MR function, therefore, we hypothesized that ERα mediates the benefits of endothelial MR deficiency. Females lacking endothelial MR or wild-type littermates were fed control or high-fat diet for 20 weeks to cause obesity. MR deletion improved mesenteric artery endothelial-dependent vasodilation in obese females, and ex vivo ERα inhibition negated this protective effect. Endothelial MR deletion resulted in significantly more ERα mRNA and protein. In vitro, estrogen increased endothelial NO synthase phosphorylation, and this was inhibited by aldosterone and dependent on MR. Both proteins coimmunoprecipitated with striatin and a mimetic peptide that disrupts ERα-striatin binding also decreased MR-striatin interaction. Finally, removing endothelial MR in obese females restored endothelial function by increasing the NO component of vasodilation. Combined deletion of endothelial ERα negated the benefit of endothelial MR deletion. These results indicate that endothelial ERα prevents the detrimental effects of MR in obesity by increasing NO to rescue vasodilation in females. MR and ERα may compete for striatin binding within endothelial cells to regulate NO. These data identify a novel mechanism that promotes MR antagonism to prevent obesity-induced microvascular dysfunction in females.

scholarly journals Blockade of angiotensin-converting enzyme or tumor necrosis factor-α reverses maternal high-fat diet-induced sensitization of angiotensin II hypertension in male rat offspring

2020 ◽  
Vol 318 (2) ◽  
pp. R351-R359 ◽  
Author(s):  
Xue-Fang Wang ◽  
Jian-Dong Li ◽  
Yan-Li Huo ◽  
Yu-Ping Zhang ◽  
Zhi-Qin Fang ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Adult Offspring ◽  
Ang Ii ◽  
Converting Enzyme ◽  
High Fat ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular diseases in adult offspring. Our previous study demonstrated that maternal HFD enhances pressor responses to ANG II or a proinflammatory cytokine (PIC), which is associated with increased expression of brain renin-angiotensin system (RAS) components and PICs in adult offspring. The present study further investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) blocks sensitization of ANG II hypertension in offspring of HFD dams. All offspring were bred from dams with normal fat diet (NFD) or HFD starting two weeks before mating and maintained until weaning of the offspring. Then the weaned offspring were treated with an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water through the end of testing with a slow-pressor dose of ANG II. RT-PCR analyses of the lamina terminalis and paraventricular nucleus revealed upregulation of mRNA expression of several RAS components and PICs in male offspring of HFD dams when compared with age-matched offspring of NFD dams. The enhanced gene expression was attenuated by blockade of either RAS or PICs. Likewise, ANG II administration produced an augmented pressor response in offspring of HFD dams. This was abolished by either ACE or TNF-α inhibitor. Taken together, this study provides mechanistic evidence and a therapeutic strategy that systemic inhibition of the RAS and PICs can block maternal HFD-induced sensitization of ANG II hypertension, which is associated with attenuation of brain RAS and PIC expression in offspring.

scholarly journals The Protective Role of Sestrin2 in High Fat Diet-Induced Nephropathy

2020 ◽  
Author(s):  
Abdelali Agouni ◽  
Duck Y Lee ◽  
Assaad A Eid ◽  
Yves Gorin ◽  
Kumar Sharma
Keyword(s):  
Fatty Acid ◽  
Mouse Model ◽  
High Fat Diet ◽  
Chow Diet ◽  
Pathological Feature ◽  
Lipid Uptake ◽  
Wild Type ◽  
High Fat ◽  
Obesity And Diabetes ◽  
The Impact

Introduction: Obesity is a major risk factor for type-2 diabetes predisposing patients to diabetic nephropathy (DN), the leading cause of end-stage renal failure. Glomerular injury is a prominent pathological feature of DN. Sestrin2 (Sesn2) is a stress-induced protein, but its role in DN has not been investigated. Therefore, we have determined the impact of Sesn2 deletion in a mouse model of obesityinduced nephropathy. Materials and methods: We examined the effects of Sesn2-deficiency in a longterm (22 weeks) mouse model of high fat diet (HFD)-induced obesity on glomerular structure. The severity of renal injury and fibrosis in wild type (Sesn2+/+) mice (fed HFD or chow diets) was compared to that in Sesn2-deficient mice (Sesn2-/- ) fed HFD or chow diets. Animal work was carried out under an IACUC-approved protocol. Results: Data showed that Sesn2 ablation exacerbated HFD-induced glomerular fibrotic injury as evidenced by mesangial matrix hypertrophy and accumulation of both fibronectin and collagen IV. Western blot analysis revealed that HFD- or chow-fed Sesn2-/- mice exhibited higher protein expression of key lipogenic enzymes, fatty acid translocase CD36 (an indicator of lipid uptake), fatty acid synthase and ATP citrate lyase. Sesn2-deficiency in obese mice resulted in podocyte loss as indicated by reduced expression of synaptopodin. Glomerular lesions like those observed in HFD-fed wild-type mice were detected in Sesn2-/-mice fed a chow diet, indicating that the basal deletion of Sesn2 is deleterious by itself. Conclusions: We provide the first evidence that Sesn2 is renoprotective in obesity-induced nephropathy by diminishing lipid accumulation and blocking excessive lipid uptake and de novo lipid synthesis. Understanding the protective of Sesn2 should yield novel therapeutic interventions to effectively preserve glomerular function in obesity and diabetes.

scholarly journals Novel interaction of antioxidant-1 with TRAF4: role in inflammatory responses in endothelial cells

2019 ◽  
Vol 317 (6) ◽  
pp. C1161-C1171
Author(s):  
Archita Das ◽  
Varadarajan Sudhahar ◽  
Masuko Ushio-Fukai ◽  
Tohru Fukai
Keyword(s):  
Endothelial Cells ◽  
High Fat Diet ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Oxygen Species ◽  
High Fat ◽  
Inflammatory Gene Expression ◽  
Tnf Α

NADPH oxidase (NOX)-derived reactive oxygen species (ROS) and copper (Cu), an essential micronutrient, have been implicated in vascular inflammatory diseases. We reported that in proinflammatory cytokine TNF-α-stimulated endothelial cells (ECs), cytosolic Cu chaperone antioxidant-1 (Atox1) functions as a Cu-dependent transcription factor for the NOX organizer p47phox, thereby increasing ROS-dependent inflammatory gene expression. However, the role and mechanism of Atox1 nuclear translocation in inflamed ECs remain unclear. Using enface staining and nuclear fractionation, here we show that Atox1 was localized in the nucleus in inflamed aortas from ApoE−/− mice with angiotensin II infusion on a high-fat diet, while it was found in cytosol in those from control mice. In cultured human ECs, TNF-α stimulation promoted Atox1 nuclear translocation within 15 min, which was associated with Atox1 binding to TNF-α receptor-associated factor 4 (TRAF4) in a Cu-dependent manner. TRAF4 depletion by siRNA significantly inhibited Atox1 nuclear translocation, p47phox expression, and ROS production as well as its downstream VCAM1/ICAM1 expression and monocyte adhesion to inflamed ECs, which were rescued by overexpression of nuclear targeted Atox1. Furthermore, Atox1 colocalized with TRAF4 at the nucleus in TNF-α-stimulated inflamed ECs and vessels. In summary, Cu-dependent Atox1 binding to TRAF4 plays an important role in Atox1 nuclear translocation and ROS-dependent inflammatory responses in TNF-α-stimulated ECs. Thus the Atox1-TRAF4 axis is a novel therapeutic target for vascular inflammatory disease such as atherosclerosis.

IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet

2013 ◽  
Vol 305 (12) ◽  
pp. G891-G899 ◽  
Author(s):  
Xiao-Yu Luo ◽  
Terumi Takahara ◽  
Kengo Kawai ◽  
Masayuki Fujino ◽  
Toshiro Sugiyama ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Wild Type ◽  
High Fat ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor

Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.

scholarly journals Ghrelin Stimulates Endothelial Cells Angiogenesis through Extracellular Regulated Protein Kinases (ERK) Signaling Pathway

2018 ◽  
Vol 19 (9) ◽  
pp. 2530 ◽  
Author(s):  
Jun Wang ◽  
Lin He ◽  
Bahetiyaer Huwatibieke ◽  
Lingchao Liu ◽  
He Lan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adipose Tissue ◽  
Signaling Pathway ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Erk Signaling ◽  
Wild Type ◽  
High Fat ◽  
And Migration ◽  
Extracellular Regulated Protein Kinases

Adipose tissue is hyper-vascularized. Vessels in adipose tissue not only supply nutrients and oxygen to nourish adipocytes, but also provide cytokines that regulate mass and function of adipose tissue. Understanding the fundamental mechanisms how vessels modulate adipocyte functions would provide new therapeutic options for treatment of metabolic disease and obesity. In recent years, researches about ghrelin are focused on glucose and lipid metabolism, but its effect on vascular function remains uncharacterized. In the present study, ghrelin receptor gene deletion mice (Ghsr−/− mice) were used to study ghrelin-regulated vascular metabolism in white adipose tissue. Ghsr−/− mice demonstrated lower food intake, lower body weight, and resistance to high-fat diet-induced obesity. The number of vessels in white adipose tissue was decreased in Ghsr−/− mice when compared with wild type mice fed with high-fat diet. To further define ghrelin effects in vitro, we used endothelial progenitor cells from wild type and Ghsr−/− mice as well as human umbilical vein endothelial cells in our experiments. We found that ghrelin stimulated endothelial cells angiogenesis and migration through the MEK-ERK signaling pathway. [d-Lys3]-GHRP-6 and PD98059 could reverse the effects of ghrelin on endothelial cells. Our study indicates that ghrelin activates its receptor on endothelial cells to promote angiogenesis and migration via a mechanism involving the extracellular regulated protein kinases (ERK) signaling pathway.

Sex differences in response to a high fat diet in an Alzheimer’s Disease mouse model

2018 ◽  
Author(s):  
Alejandra Freire Fernández-Regatillo ◽  
María L. de Ceballos ◽  
Jesús Argente ◽  
Sonia Díaz Pacheco ◽  
Clara González Martínez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sex Differences ◽  
Mouse Model ◽  
High Fat Diet ◽  
High Fat
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