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      Myeloma Light Chain-Induced Renal Injury in Mice

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          Abstract

          We investigated the effects of human light chain (LC) protein-overload in mice kidney to gain further insights into the molecular mechanisms involved in the pathogenesis of myeloma kidney. Intact male C57BL/6, 10- to 12-week-old mice were given daily intraperitoneal (i.p.) injections of 1 ml of human ĸ -LCs (1.5 mg/ml, low dose), or (100 mg/ml, high dose) to uninephrectomized mice for 2 weeks. Intact, sham-operated or uninephrectomized control animals were given the same volume (1 ml/day) of saline, human serum albumin (10 mg/ml) or bovine serum albumin (100 mg/ml) i.p. for 2 weeks in place of LCs. The low-dose LC-treated mice had human LCs in their urine and a significant increase in monocyte chemoattractant protein-1 (MCP-1) mRNA in the kidneys. Uninephrectomized mice treated with high-dose ĸ-LCs showed tubule casts, and foci of intracytoplasmic rhomboid crystals within the proximal tubules, along with cytoskeletal disruptions and alterations in the brush-border membrane, and high concentrations of human ĸ-LC were present in their sera. High-dose LC treatment also led to increases in serum creatinine and tumor necrosis factor-α levels, and marked increases in interleukin-6 and MCP-1 expression as well as cellular apoptosis in the kidneys. These studies demonstrate that myeloma LC overload over a range of LC concentrations in mice causes significant functional and morphological kidney injury. The model should be helpful in investigating pathophysiologic mechanisms and exploring therapeutic interventions for myeloma kidney and other LC-associated renal disorders.

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          Most cited references20

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          Pathophysiology of progressive nephropathies.

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            Why is proteinuria an ominous biomarker of progressive kidney disease?

            Progressive tubule injury and interstitial fibrosis frequently accompany glomerulopathies associated with proteinuria. Clinical experience indicates that higher levels of proteinuria prior to, as well as after initiation of treatment predict more rapid decline in renal function and more pronounced tubulointerstitial injury. It has been proposed that filtration of potentially tubulotoxic plasma proteins is responsible for the observed correlations between proteinuria and progression (i.e., proteinuria is a cause and not only a consequence of progressive renal injury). Numerous attempts have been made to identify the species of putative tubulotoxic proteins in this progressive injury process, but much uncertainty persists. These uncertainties stem from nonphysiologic exposure of apical cell surfaces to proteins in vitro, the extremely high concentrations of various proteins tested in vitro, and the nonuniformity of end points measured. Furthermore, there is often a lack of correlation between in vitro and in vivo findings, and a lack of uniformity of results even for seemingly similar in vitro experiments. Less controversy is evident in the potential pathways whereby injured tubules evoke a tubulointerstitial inflammatory and fibrotic response, with many in vivo models serving to incriminate excessive cytokine and chemokine production, infiltration of various inflammatory cells, and the balance between apoptosis and cell proliferation. Despite many years of concerted efforts, we believe it is still unclear whether proteinuria is a cause (and if so, which species of protein), or only a consequence of progressive renal injury. Nevertheless, pending the resolution of these uncertainties by more decisive and unambiguous experimentation, the strongly predictive inverse relationship between level of proteinuria and long-term renal survival currently justifies aggressive antiproteinuric treatment strategies, with a goal of reducing protein excretion rate to the lowest level possible without the induction of symptoms or undue risk.
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              Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis.

              Monocyte chemoattractant protein-1 (MCP-1) is upregulated in renal parenchymal cells during kidney disease. To investigate whether MCP-1 promotes tubular and/or glomerular injury, we induced nephrotoxic serum nephritis (NSN) in MCP-1 genetically deficient mice. Mice were analyzed when tubules and glomeruli were severely damaged in the MCP-1-intact strain (day 7). MCP-1 transcripts increased fivefold in MCP-1-intact mice. MCP-1 was predominantly localized within cortical tubules (90%), and most cortical tubules were damaged, whereas few glomerular cells expressed MCP-1 (10%). By comparison, there was a marked reduction (>40%) in tubular injury in MCP-1-deficient mice (histopathology, apoptosis). MCP-1-deficient mice were not protected from glomerular injury (histopathology, proteinuria, macrophage influx). Macrophage accumulation increased adjacent to tubules in MCP-1-intact mice compared with MCP-1-deficient mice (70%, P < 0.005), indicating that macrophages recruited by MCP-1 induce tubular epithelial cell (TEC) damage. Lipopolysaccharide-activated bone marrow macrophages released molecules that induced TEC death that was not dependent on MCP-1 expression by macrophages or TEC. In conclusion, MCP-1 is predominantly expressed by TEC and not glomeruli, promotes TEC and not glomerular damage, and increases activated macrophages adjacent to TEC that damage TEC during NSN. Therefore, we suggest that blockage of TEC MCP-1 expression is a therapeutic strategy for some forms of kidney disease.
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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
                2010
                September 2010
                29 June 2010
                : 116
                : 2
                : e32-e41
                Affiliations
                aSection of Nephrology and Hypertension and bPeptide Research Laboratory, Department of Medicine, Tulane University School of Medicine, and cSoutheast Louisiana Veterans Health Care System, US Department of Veterans Affairs, New Orleans, La., USA
                Article
                317129 Nephron Exp Nephrol 2010;116:e32–e41
                10.1159/000317129
                20588062
                7ff39a46-b469-43ad-aa61-1c2c88dcc8db
                © 2010 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.

                History
                : 15 September 2009
                : 09 March 2010
                Page count
                Figures: 7, References: 37, Pages: 1
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Protein overload,Kidney failure,Proteinuria,Plasma cell dyscrasias,Cytokines

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