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      High Glucose Enhances oxLDL-Induced Apoptosis in Human Renal Proximal Tubular Epithelial Cells Largely via Inducing Lectin-Like ox-LDL Receptor-1

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          Background: High blood glucose is characteristic of diabetic nephropathy (DN). Both lectin-like ox-LDL receptor-1 (LOX-1) and renal tubular epithelial cells apoptosis reportedly are important for the pathogenesis and progression of DN. In this study, we explored the regulatory effects of high glucose on the expression of LOX-1 and its impact on oxLDL-induced apoptosis in human renal proximal tubular epithelial cells (HRPTEpCs). Methods: Primary HRPTEpCs were treated with high glucose with or without concurrent treatment with selective p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 or lentiviral knockdown of LOX-1. HRPTEpCs cultured in normal glucose concentration (5.5 mmol/l) was used as a control. Results and Conclusion: High glucose concentration dependency increased the expression of LOX-1, which led to increased ox-LDL binding in HRPTEpCs. In addition, high glucose upregulated the LOX-1 gene promoter activity but not its mRNA stability in HRPTEpCs; the effect was abolished by PD169316. Furthermore, high glucose markedly enhanced oxLDL-induced apoptosis in HRPTEpCs, which was largely abolished by knockdown of LOX-1. This study demonstrates that high glucose induces the expression of LOX-1 at the gene promoter/transcription level mainly by a p38 MAPK-dependent mechanism, which enhances oxLDL-induced apoptosis in renal tubular epithelial cells. It adds new insights into the molecular mechanisms underlying DN.

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          Most cited references 12

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

           K Livak,  T Schmittgen (2001)
          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function.

            Previous studies have demonstrated that interleukinalpha (IL-1alpha) inhibits glucocorticoid receptor (GR) nuclear translocation and dexamethasone (Dex)-induced gene transcription. Given that IL-1alpha is a potent activator of the p38 mitogen-activated protein kinase (MAPK) signal transduction pathway and p38 MAPK has been associated with reduced GR function, we examined the role of p38 MAPK in IL-1alpha-mediated inhibition of GR function in mouse fibroblast cells stably transfected with a GR-mediated reporter gene construct (LMCAT cells). Treatment of LMCAT cells with IL-1alpha (1000 U/ml) for 24 h inhibited Dex (50 nM)-induced GRE-CAT activity by approximately 35%. When cells were cotreated for 24 h with IL-1alpha plus SB-203580 (0.5-1 microM), a selective p38 inhibitor, IL-1alpha's inhibitory effect on GR function as determined by Dex-induced GRE-CAT activity was reversed. Using gel mobility shift assay, SB-203580 was also found to reverse IL-1alpha inhibition of GR-GRE binding. Further confirming the role of p38 pathways, pretreatment of LMCAT cells with antisense oligonucleotides targeted to p38 MAPK completely abrogated IL-1alpha inhibition of Dex-induced GRE-CAT activity. Taken together, these results demonstrate that activation of p38 MAPK pathways are involved in IL-1alpha-mediated inhibition of GR function. In addition, these findings extend the intracellular targets of p38 to include the GR and indicate that p38 inhibitors may have special utility in immunologic and/or neuropsychiatric disorders associated with impaired GR-mediated feedback inhibition.
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              Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes.

               G Tonolo,  R Nosadini (2011)
              Oxidized lipids initiate and modulate the inflammatory cellular events in the arterial wall and the formation of macrophage foam cells. CD36 mediates the cellular uptake of ox-LDL through its recognition of specific truncated fatty acid moieties and oxidized phosphatidylcholine. Evidence has been reported that chemokine CXCL16, rather than CD36, is the main scavenger receptor in human podocytes mediating the uptake of ox-LDL. Ox-LDL induces loss of nephrin expression from cultured podocytes. It has been recently shown that nephrin once phosphorilated associates with PI3K and stimulates the Akt dependent signaling. This pathway plays a critical role in nephrin-actin-dependent cytoskeleton activation and remodeling, in the control of protein trafficking and in podocyte survival. An enhanced FFA uptake by podocytes is mediated by increased C36 scavenger receptor expression, together with a decrease of betaoxidation and in turn intracellular lipid accumulation. Accumulated FFA that is trapped into the mitochondrial matrix leads to mitochondrial ROS production, lipid peroxidation and mitochondrial damage and dysfunction. A disturbed transport and oxidation of FFA, paralleled by an impaired antioxidant response, damages podocyte structure and leads to glomerulopathy in early stages of nephrosis. Increased triglyceride synthesis and ox-and glycated LDL uptake by mesangial cells may also contribute to determine diabetic glomerulopathy. Oxidative processes are pivotal events in injury to renal tubular and epithelial cells exposed to ox-LDL. Notably CXCL16 are the main receptors for the uptake of ox-LDL in podocytes, whereas CD36 plays this role in tubular renal cells. In overt type 2 diabetes Ox-LDL and FFA damage podocyte function, SD-podocyte structure and tubulointerstitial tissue, at least partially, through different pathogenetic mechanisms. Further studies are needed to investigate the role of Ox-LDL and FFA on renal complications in obese, insulin resistant patients before the development of diabetes. The aim of the present review is to briefly elucidate the patterns of systemic lipid metabolism and the individual effects of lipotoxicity at glomerular and tubular level in the kidney of overt type 2 diabetic patients. These findings better elucidate our knowledge of diabetic glomerulopathy, beside and along with previous findings, in vivo and in vitro, on ox-LDL and FFA effects in mesangial cells. Copyright © 2010 Elsevier B.V. All rights reserved.

                Author and article information

                Departments of aGeriatrics and bRehabilitation, The Second Xiangya Hospital, Central South University, Changsha, China
                S. Karger AG (Basel, Switzerland karger@ )
                June 2016
                23 March 2016
                : 98
                : 1-2
                : 20-28
                PHA20160981-2020 10.1159/000444934 27003929 Pharmacology 2016;98:20-28
                © 2016 S. Karger AG, Basel

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                Figures: 7, Tables: 1, References: 24, Pages: 9
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