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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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          Abstract

          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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          Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes.

          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.
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            Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney.

            A significant reduction of renal mass results in proteinuria, glomerulosclerosis, and tubulointerstitial injury, culminating in end-stage chronic renal failure (CRF). The accumulation of lipids in the kidney can cause renal disease. Uptake of oxidized lipoproteins via scavenger receptors, reabsorption of filtered protein-bound lipids via the megalin-cubilin complex, and increased glucose load per nephron can promote lipid accumulation in glomerular, tubular, and interstitial cells in CRF. Cellular lipid homeostasis is regulated by lipid influx, synthesis, catabolism, and efflux. We examined lipid-regulatory factors in the remnant kidney of rats 11 wk after nephrectomy (CRF) or sham operation. CRF resulted in azotemia, proteinuria, lipid accumulation in the kidney, upregulation of megalin, cubilin, mediators of lipid influx (scavenger receptor class A and lectin-like oxidized receptor-1), lipid efflux (liver X receptor alpha/beta and ATP-binding cassette transporter), and fatty acid biosynthesis (carbohydrate-response element binding protein, fatty acid synthase, and acetyl-CoA carboxylase). However, factors involved in cholesterol biosynthesis (sterol regulatory element binding protein, 3-hydroxy-3-methylglutaryl coenzyme A reductase, SCAP, Insig-1, and Insig-2) and fatty acid oxidation (peroxisome proliferator-activated receptor, acyl-CoA oxidase, and liver-type fatty acid binding protein) were reduced in the remnant kidney. Thus CRF results in heavy lipid accumulation in the remnant kidney, which is mediated by upregulation of pathways involved in tubular reabsorption of filtered protein-bound lipids, influx of oxidized lipoproteins and synthesis of fatty acids, and downregulation of pathways involved in fatty acid catabolism.
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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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                Author and article information

                Journal
                PHA
                Pharmacology
                10.1159/issn.0031-7012
                Pharmacology
                Pharmacology
                S. Karger AG (Basel, Switzerland karger@ 123456karger.com http://www.karger.com )
                0031-7012
                1423-0313
                June 2016
                23 March 2016
                : 98
                : 1-2
                : 20-28
                Affiliations
                Departments of aGeriatrics and bRehabilitation, The Second Xiangya Hospital, Central South University, Changsha, China
                Article
                PHA20160981-2020 Pharmacology 2016;98:20-28
                10.1159/000444934
                27003929
                c48b1dc4-b4a2-40fe-90e2-f321327e6da3
                © 2016 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 08 December 2015
                : 23 February 2016
                Page count
                Figures: 7, Tables: 1, References: 24, Pages: 9
                Categories
                Original Paper

                Medicine,General social science
                High glucose,Diabetic nephropathy,Lectin-like ox-LDL receptor-1,Oxidized LDL,Renal proximal tubular epithelial cell,Apoptosis

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