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      Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRα pathway in HK-2 cells

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          Abstract

          The dysregulation of cholesterol metabolism and inflammation plays a significant role in the progression of diabetic nephropathy (DN). Anthocyanins are polyphenols widely distributed in food and exert various biological effects including antioxidative, anti-inflammatory, and antihyperlipidemic effects. However, it remains unclear whether anthocyanins are associated with DN, and the mechanisms involved in the reciprocal regulation of inflammation and cholesterol efflux are yet to be elucidated. In this study, we evaluated the regulation of cholesterol metabolism and the anti-inflammatory effects exerted by anthocyanins (cyanidin-3-O-β-glucoside chloride [C3G] or cyanidin chloride [Cy]) and investigated the underlying molecular mechanism of action using high-glucose (HG)-stimulated HK-2 cells. We found that anthocyanins enhanced cholesterol efflux and ABCA1 expression markedly in HK-2 cells. In addition, they increased peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptor alpha (LXRα) expression and decreased the HG-induced expression of the proinflammatory cytokines intercellular adhesion molecule-1 (ICAM1), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-β1 (TGFβ1), as well as NFκB activation. Incubation with the PPARα-specific inhibitor GW6471 and LXRα shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPARα-LXRα-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXRα abrogated the anti-inflammatory effect of anthocyanins, whereas the PPARα antagonist GW6471 does not have this effect. Further investigations revealed that LXRα might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGFβ1 expression by reducing the nuclear translocation of NFκB. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXRα pathway-induced inflammatory response might be one of the main mechanisms by which anthocyanins exert their protective effects in DN.

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          Most cited references 39

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          MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy.

           H. Tesch (2008)
          Despite current therapies, many diabetic patients will suffer from declining renal function in association with progressive kidney inflammation. Recently, animal model studies have demonstrated that kidney macrophage accumulation is a critical factor in the development of diabetic nephropathy. However, specific anti-inflammatory strategies are not yet being considered for the treatment of patients with diabetic renal injury. This review highlights the chemokine monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine ligand 2 as a major promoter of inflammation, renal injury, and fibrosis in diabetic nephropathy. Researchers have found that diabetes induces kidney MCP-1 production and that urine MCP-1 levels can be used to assess renal inflammation in this disease. In addition, genetic deletion and molecular blocking studies in rodents have identified MCP-1 as an important therapeutic target for treating diabetic nephropathy. Evidence also suggests that a polymorphism in the human MCP-1 gene is associated with progressive kidney failure in type 2 diabetes, which may identify patients at higher risk who need additional therapy. These findings provide a strong rationale for developing specific therapies against MCP-1 and inflammation in diabetic nephropathy.
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            NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy.

            Nuclear factor-kappaB (NF-kappaB) regulates genes involved in renal disease progression, such as the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES. NF-kappaB is activated in experimental models of renal injury, and in vitro studies also suggest that proteinuria and angiotensin II could be important NF-kappaB activators. It has been proposed that locally produced MCP-1 may be involved in the development of diabetic nephropathy (DN). We examined the hypothesis that NF-kappaB could be an indicator of renal damage progression in DN. Biopsy specimens from 11 patients with type 2 diabeties and overt nephropathy were studied by southwestern histochemistry for the in situ detection of activated NF-kappaB. In addition, by immunohistochemistry and/or in situ hybridization, we studied the expression of MCP-1 and RANTES, whose genes are regulated by NF-kappaB. NF-kappaB was detected mainly in cortical tubular epithelial cells and, to a lesser extent, in some glomerular and interstitial cells. A strong upregulation of MCP-1 and RANTES was observed in all the cases, mainly in tubular cells, and there was a strong correlation between the expression of these chemokines and NF-kappaB activation in the same cells, as observed in serial sections (r = 0.7; P = 0.01). In addition, the tubular expression of these chemokines was correlated mainly with the magnitude of the proteinuria (P = 0.002) and with interstitial cell infiltration (P<0.05). The activation of NF-kappaB and the transcription of certain pro-inflammatory chemokines in tubular epithelial cells are markers of progressive DN. Proteinuria might be one of the main factors inducing the observed pro-inflammatory phenotype.
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              Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes.

              In Akita and OVE26 mice, two genetic models of type 1 diabetes, diabetic nephropathy is characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis and proteinuria, and is associated with increased expression of profibrotic growth factors, proinflammatory cytokines, and increased oxidative stress. We have also found significant increases in renal triglyceride and cholesterol content. The increase in renal triglyceride content is associated with 1) increased expression of sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP), which collectively results in increased fatty acid synthesis, 2) decreased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and -delta, which results in decreased fatty acid oxidation, and 3) decreased expression of farnesoid X receptor (FXR) and small heterodimer partner (SHP). The increase in cholesterol content is associated with 1) increased expression of SREBP-2 and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which results in increased cholesterol synthesis, and 2) decreased expression of liver X receptor (LXR)-alpha, LXR-beta, and ATP-binding cassette transporter-1, which results in decreased cholesterol efflux. Our results indicate that in type 1 diabetes, there is altered renal lipid metabolism favoring net accumulation of triglycerides and cholesterol, which are driven by increases in SREBP-1, ChREBP, and SREBP-2 and decreases in FXR, LXR-alpha, and LXR-beta, which may also play a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                04 September 2015
                : 9
                : 5099-5113
                Affiliations
                [1 ]Department of Pathology, Hebei Medical University, Shijiazhuang, People’s Republic of China
                [2 ]Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People’s Republic of China
                Author notes
                Correspondence: Huijun Duan, Department of Pathology, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei 050017, People’s Republic of China, Fax +86 311 8626 6942, Email duanhj999@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-9-5099
                10.2147/DDDT.S90201
                4567235
                © 2015 Du et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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