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      Animal Models of Light Chain Deposition Disease Provide a Better Understanding of Nodular Glomerulosclerosis

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          Abstract

          Background: Light chain deposition disease (LCDD) is a model of glomerulosclerosis. The mature lesion of LCDD mimics nodular glomerulosclerosis in diabetic nephropathy. The pathogenetic mechanisms involved are similar in both disorders, though the causative factors are entirely different. This fact highlights the generic response of the mesangium to varied stimuli. In-vitro work has provided much insight into the pathogenesis of glomerulosclerosis in LCDD where the mesangium is the main target for initiation and progression of the disease. The lack of animal models has prevented the development of further therapeutic approaches to be tested in platforms such as ex-vivo and in-vivo preparing the way for human studies. Methods: Light chains (LCs) obtained from the urine of patients with renal biopsy proven LCDD were delivered to glomeruli using ex-vivo and in-vivo approaches to address whether in-vitro information could be validated in-vivo. Selected in-vitro studies were conducted to address specific issues dealing with mesangial cell (MC) differentiation and composition of extracellular matrix to add additional data to the existing vast literature. Using light, electron and scanning microscopy together with immunohistochemistry and ultrastructural immunolabeling, MCs incubated in Matrigel with LCDD LCs, as well as delivery of such LCs by perfusion via renal artery (ex-vivo) and penile dorsal vein (in-vivo) to the kidneys, validation of pathogenetic pathways previously suggested in in-vitro experiments were tested and confirmed. Results: The animal models described in this manuscript provide validation for the in-vitro data that have been previously published and expand our appreciation of the important role that caveolin-1 plays in signaling events essential for the downstream sequence of events that eventually leads to the pathological alterations centered in the mesangium characterized by an increase in matrix production and formation of mesangial nodules. Conclusions: The same findings observed in renal biopsies of patients with LCDD (mesangial expansion with increased matrix) were documented in the ex-vivo and in-vivo platforms. In-vivo understanding of the pathogenesis of mesangial glomerulosclerosis, as accomplished in the reported research, is crucial for the design of novel therapeutic approaches to treat a number of glomerulopathies with similar pathogenetic mechanisms. Inhibiting interactions between glomerulopathic LCs and MCs or interrupting the protein production/secretion pathways are potentially effective therapeutic maneuvers. The results obtained with caveolin-1 knockout mice emphasized the importance of caveolin-1 in signaling events essential to effect downstream mesangial alterations.

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          Most cited references29

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          Drying cells for SEM, AFM and TEM by hexamethyldisilazane: a study on hepatic endothelial cells.

          Critical point drying (CPD) is a common method of drying biological specimens for scanning electron microscopy (SEM). Drying by evaporation of hexamethyldisilazane (HMDS) has been described as a good alternative. This method, however, is infrequently used. Therefore, we reassessed HMDS drying. Cultured rat hepatic sinusoidal endothelial cells (LEC), possessing fragile fenestrae and sieve plates, were subjected to CPD and HMDS drying and evaluated in the scanning electron microscope, atomic force microscope (AFM) and transmission electron microscope (TEM). We observed no differences between the two methods regarding cellular ultrastructure. In contrast with CPD, HMDS drying takes only a few minutes, less effort, low costs for chemicals and requires no equipment. We conclude that HMDS-dried specimens have equal quality to CPD ones. Furthermore, the method also proved useful for drying whole-mount cells for TEM and AFM.
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            AL-amyloidosis and light-chain deposition disease light chains induce divergent phenotypic transformations of human mesangial cells.

            Human mesangial cells (HMCs) are injured by either excessive amounts or abnormal light chains (LCs), or a combination of both in patients with plasma cell dyscrasias. Consequently, these HMCs undergo phenotypic transformations. HMCs were incubated with eight different light-chains (LCs) for 96 h. These cells, in addition to 51 patient samples from patients with AL-amyloidosis (AL-Am), light-chain deposition disease (LCDD), myeloma cast nephropathy (MCN) and controls were analyzed by immunohistochemistry for CD68, muscle-specific actin (MSA), smooth muscle actin (SMA), CD14, and Ham56 protein expressions. All samples were also studied using electron microscopy. Greater staining (four- and three-fold) expressions of CD68 and Ham56, respectively, were observed in the HMCs incubated with AL-Am-LCs compared to those with LCDD-LCs and control. SMA expression levels were five-fold higher in LCDD-LC-treated cells compared to the other categories of LC-treated and control cells. Similar results were obtained in the renal specimens, however, CD68 levels were 12-fold higher in the AL-Am cases compared to the LCDD cases, respectively. Conversely, MSA and SMA levels were three fold higher in the LCDD cases than in the AL-Am ones. No CD14 expression was noted in any of the samples and CD-34 staining of HMCs treated with the various LCs only showed rare positive cells. Dynamic real-time studies to visualize the rough endoplasmic reticulum (RER) and lysosomal compartments in HMCs incubated with LCDD and AL-Am-LCs showed striking expansion of each of the above-mentioned compartments, respectively. This indicates the presence of more RER in the LCDD-LC-treated HMCs and a striking increase in lysosomes noticeable in the AL-Am-LC-treated cells. Data obtained in this study highlighted that HMCs incubated with LCDD-LCs undergo a myofibroblastic phenotypic transformation, while AL-Am-LCs induce a macrophage-like phenotype in these cells.
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              Manifestations of systemic light chain deposition.

              In two patients with terminal renal failure, manifestations of disease developed in multiple organ systems. One had a previous diagnosis of multiple myeloma with kappa light chain proteinemia and proteinuria. The other had idiopathic lobular glomerulonephritis. Hepatic and neurologic abnormalities developed in both; in the latter gastrointestinal, cardiac and endocrine disease developed as well. Clinical and pathologic correlations suggest that the retention and tissue deposition of light chains produced the organ dysfunction, inasmuch as free kappa light chain determinants were demonstrated histologically in the clinically affected organs. The deposition in these patients may be an extreme example of a common but previously unrecognized form of plasma cell dyscrasia.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                Nephron
                S. Karger AG (Basel, Switzerland karger@ 123456karger.com http://www.karger.com )
                1660-8151
                2235-3186
                February 2016
                22 January 2016
                : 132
                : 2
                : 119-136
                Affiliations
                aDepartments of Pathology and Translational Pathobiology, bAnatomy and Cellular Biology, and cMedicine, Louisiana State University Health Sciences Center, Shreveport, La., USA
                Article
                NEF2016132002119 Nephron 2016;132:119-136
                10.1159/000443282
                26794829
                091ae144-510c-4fdb-94d7-cdd7473ccff4
                © 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
                : 28 April 2015
                : 06 December 2015
                Page count
                Figures: 16, References: 34, Pages: 18
                Categories
                Experimental Nephrology and Genetics: Original Paper

                Medicine,General social science
                Light chain deposition disease,Immunoglobulin light chain,Pathogenesis,Mesangium

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