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      Pravastatin Inhibits Carboxymethyllysine-Induced Monocyte Chemoattractant Protein 1 Expression in Podocytes via Prevention of Signalling Events

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          Abstract

          Background: Up-regulation of local monocyte chemoattractant protein 1 (MCP-1) production is involved in glomerular damage through macrophage recruitment and activation in diabetic nephropathy. Advanced glycation end-products induced chemokine production in cultured mesangial cells and podocytes. Statins prevented recruitment of macrophages to the glomeruli, suggesting that statins may have the ability of anti-inflammation. In the present studies, we investigated the effects of pravastatin in the carboxymethyllysine (CML)-induced MCP-1 expression in mouse differentiated podocytes. Methods: MCP-1 gene and protein expressions were examined using RT-PCR and ELISA. Dichlorofluorescein-sensitive intracellular reactive oxygen species (ROS) generation was measured by confocal microscopy. Activation of extracellular signal-regulated kinase (ERK), nuclear factor (NF) ĸB and Sp1 were studied using Western blotting and immunocytochemistry. Results: MCP-1 was induced by CML in a time- and dose-dependent manner. CML-induced MCP-1 mRNA and protein production were inhibited by 0.1 or 1 m M pravastatin. CML rapidly generated intracellular ROS in podocytes.Pravastatin did not have any ability of blocking ROS generation. Phosphorylated ERK was found in podocytes incubated with CML and was prevented by pravastatin in a dose-dependent manner. Both Western blotting and immunocytochemistry results suggested that pretreatment of podocytes with pravastatin prevented the CML-induced NF-ĸB and Sp1 translocation. Conclusion: These results suggest that pravastatin prevents CML to induce MCP-1 expression in podocytes via modulation of the intracellular ERK/NF-ĸB and Sp1 signalling pathway.

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          Most cited references 29

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          Structure, regulation and function of NF-kappa B.

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            From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy.

            Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. TGF-beta1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman's capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.
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              Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.

              Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2007
                May 2007
                07 March 2007
                : 106
                : 1
                : e1-e10
                Affiliations
                aRenal Division, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China; bDivision of Nephrology, Department of Internal Medicine, Juntendo University, School of Medicine, Tokyo, Japan
                Article
                100498 Nephron Exp Nephrol 2007;106:e1–e10
                10.1159/000100498
                17347584
                © 2007 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. 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.

                Page count
                Figures: 6, References: 39, Pages: 1
                Categories
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