Experimental Models for Renal Diseases

G. A. Herrera

• Publisher: S. Karger
• Year: 2011
• ISBN:
  9783805595384
• Topic: Medicine
• Subtopic: Nephrology

Our understanding of the pathogenesis of renal diseases and the ability to accurately classify and diagnose them has improved considerably over the last two decades. Until now, however, this information has not been available in a single, up-to-date and succinct yet comprehensive source. The publication at hand aims at filling this gap, condensing a vast amount of information into easily accessible chapters.After a discussion of basic concepts and principles of renal tissue reactions to injurious agents using a specific cell/compartment approach, a multitude of disorders are looked at, including renal interstitial fibrosis, glomerulosclerosis, various forms of glomerulonephritis and nephropathy, amyloidosis and renal Fanconi syndrome. Some of the chapters address controversial subjects, reporting the current situation and showing areas of future potential research interest. At the end of many of the contributions, a summary is provided, often in the form of a chart to facilitate the understanding of the information and to make it most useful for didactic purposes.This book is intended for students of various disciplines, as well as clinicians and investigators and all those trying to correlate basic research information with clinical issues.

Herrera GA (ed): Experimental Models for Renal Diseases: Pathogenesis and Diagnosis.
Contrib Nephrol. Basel, Karger, 2011, vol 169, pp 126-152

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Prospects and Perspectives on IgA Nephropathy from Animal Models

Steven N. Emancipator

Louis Stokes Cleveland DVA Medical Center, and Case Western Reserve University, Department of Pathology, Cleveland, Ohio, USA

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Abstract

The focus of this chapter is a systematic and critical review of the insights that experimental models have contributed to our understanding of IgA nephropathy (IgAN). We consider the generation of IgA subject to glomerular deposition, the partitioning of IgA between the circulation and glomeruli, the clearance of IgA and complexes containing IgA from the circulation, the ‘upstream’ effectors of glomerular pathophysiology, the inflammatory mediators that connect intraglomerular stimuli to functional and morphologic effects, and the contribution of animal models to our current understanding of the role that glycosylation of IgA plays in the genesis of IgAN. In each of these subsections, the evidence in favor of each principle or hypothesis is weighed in consideration of other potentially contradictory evidence and relevant issues related to IgAN in patients. The key limitations of each model system are presented, and where possible, reconciliation of discrepant observations are proposed. Subsequently, a synopsis of spontaneous models that do not offer particular mechanistic insights, and a compilation of experimental therapeutic initiatives, are reviewed. In all respects, the discussion of observations in patients or cells in vitro is limited to points where these data impinge upon interpretation of the data derived from the animal models.

Copyright © 2011 S. Karger AG, Basel

Basic Model Systems

IgA nephropathy (IgAN) is a common but complex disease that, 40 years after its recognition, still evades clear insight to its genesis despite intensive multinational efforts. Many animal models of IgAN have accrued as a result of the attempt to delineate the mechanisms operative spontaneously in patients. These models, as variable and multifaceted as IgAN in patients, are codified in this chapter.

Passive models induced by parenteral injection represent the first, and technically easiest, category of experimental IgAN. Nearly 30 years ago, Rifai et al. [1] injected immune complexes of murine myeloma IgA into mice to establish the principle that circulating IgA immune complexes can deposit within the glomerular mesangium to elicit microhematuria. They demonstrated that the dose of complexes is related to glomerular response and propensity for IgA deposition. Shortly thereafter, Isaacs and Miller [2] used the same approach with a different myeloma protein specific for the glycosidic linkage in dextran, verifying that the experimental system is not dependent upon an abnormality unique to a particular IgA paraprotein or a particular antigen or hapten carrier. This model expanded on the role of the size of immune complexes, and introduced net electrostatic charge as a factor in the site of deposition and the glomerular response to such deposition of IgA immune complexes.

Schemes designed to elicit a predominantly IgA immune response using parenteral [3, 4] or oral routes [5] produced active serum sickness models of IgAN. These active systems probed the role that immunoregulation plays in the genesis of IgAN.

Models of secondary IgAN, consequent to severe hepatocellular injury elicited by carbon tetrachloride leading to hepatic cirrhosis [6, 7], experimental surgical cholestasis [8, 9] or ethanolinduced liver disease [10] were established. These models focused awareness on the role that the rate of clearance of IgA complexes from the circulation plays in glomerular deposition and instigated recognition of unique clearance pathways applicable to IgA and perhaps IgM, but not IgG.

Technical details for establishing these early experimentally inducible models of IgAN are provided in a methods-oriented protocol handbook that is updated periodically [11]. The models of IgAN induced by dietary mycotoxins [12, 13] are cited extensively herein; these should be readily reproducible by careful reading of the original reports. Other models arise as sporadic primary glomerulonephritis or spontaneously from mutation, infection or neoplasm in species ranging from rodents and lagomorphs to higher mammals, including primates. Methodologic detail is not presented for these spontaneous forms of IgAN because experimentation requires access to the appropriate livestock. In addition to the extensively studied models of spontaneous IgAN in ddY mice [14] and the variant of these mice (HIGA) selectively inbred for high IgA production [15, 16], a few recently established transgenic mouse models raise provocative issues about the pathogenesis of IgAN [17-19]. Most spontaneous models offer little mechanistic insight, and are cited simply to chronicle their existence.

Source of IgA Depositing in Glomeruli

Immune deposits in glomeruli result from a dynamic equilibrium between accretion of Ig, either complexed with antigen or other macromolecules or as free soluble protein, and removal by catabolism or excretion into the urine (or efferent arteriole). In turn, the rate of deposition or formation of complexes within glomeruli itself depends on the production of IgA and/or IgA complexes, entry of these components into the circulation, and partitioning of the immune reactants between the glomeruli and the various clearance mechanisms. IgA is the most abundant Ig class in mammalian hosts, whether assessed by mass content or synthetic rate [reviewed in 20, 21]. However, the concentration of IgA in plasma is far less than that of IgG. These superficially contradictory facts were reconciled by recognition of a mucosal immune system, characterized by distinct lymphocyte traffic patterns and regulatory pathways. Both the synthesis and concentration of IgA are centered on mucous membranes, and their associated secretions, but extramucosal lymphoid organs also contribute (especially to IgA in the primate circulation). The various means whereby IgA in nephritogenic form are generated, as complexes or macromolecular deposits, are presented in figure 1 (left and lower center portion). Active animal models of IgAN rely on both mucosal and extramucosal cellular sources of the deposited IgA, which will be considered separately. Models characterized by overproduction of IgA not evoked by vaccination are less clear, and will be introduced within the limits of current comprehension.

Generation of IgA by Mucosal Immunization

The proclivity for mucosal immunization to drive IgA production led first to oral and subsequently nasal vaccination of mice [5, 22-38] and rats [39-47] as a means to induce active models of IgAN. Inert proteins or infectious pathogens or their products served as antigens. This diversity lends credibility to the principle that mucosal immunization by a wide range of antigens favors an IgA response in mammals generally. In other rodent systems, parenteral vaccination was supplemented by use of mucosal boosting, polarizing immunization or stimulation by superantigens [36, 38, 48], and a few models leveraged genetic predisposition to favor Th2 responses and/or IgA production [33, 49-51].

The importance of the mucosal immune response for IgA antibody production, and for genesis of IgAN, is underscored by abnormalities in mucosal structure and/or mucosal immunity in several other models of IgAN that are spontaneous, consequent to genetic manipulation, or induced by treatments distinct from vaccination, mucosal or otherwise. Specifically, transgenic overexpression of the T cell immunomodulator LIGHT leads to mucosal inflammation and diminished expression of pIgR by mucosal epithelial cells, in addition to enhanced B cell survival and IgAN [52]. The intramucosal inflammation and the reduction in pIgR-mediated IgA secretion are likely contributors to the evolution of IgAN, although this principle has not been established experimentally. Nivalenol-induced IgAN in mice [53, 54] and spontaneous IgAN in primates [55, 56] are associated with defective gut function and increased circulating antibodies specific for food antigens, especially gliadin and casein. Nivalenolinduced disease is also associated with increased antibodies specific for gut commensals and selfantigens [54], and both the specific antibodies as well as total circulating Ig pools are enriched in the IgA class, with reduced IgG and IgM. Furthermore, passive administration of monoclonal antibodies derived from mice given nivalenol induces IgAN in conventionally housed animals fed with normal chow [57].

Fig. 1. Factors that promote increased IgA production and/or altered IgA structure (left and lower center) can synergize with factors that improve access of IgA and its complexes to the glomeruli (right and upper center). Increased IgA production can be instigated by physiologic hyperstimulation of the mucosal immune system [5, 22-47], by intense stimulation of the B1 subset of (extramucosal) lymphocytes [3, 4, 62-66] or by immunomodulation of extramucosal responses. Modulators include mucosal boosting with antigen [33, 38, 48], superantigens [36, 47, 49, 85] or stimuli of innate immunity [31, 32, 34, 49, 68]. Genetic or transgenic proclivity to dysregulation of B cells by T cells [50-52, 75] and induced alterations in T cell cytokine profiles [33, 38, 77] are also recognized. Often, immune dysregulation arises from unknown mechanisms ascribed to T cells largely by intuitive guesswork [10, 30, 35-37, 44-46, 53- 56, 59- 61, 69- 72, 81]. Autoimmune and immunodeficiency diseases also frequently exhibit increased IgA synthesis and g...

Table of contents

• Cover Page
• Front Material
• Overview of Models for the Study of Renal Disease
• Mesangial Homeostasis and Pathobiology: Their Role in Health and Disease
• Parietal Epithelial Cells: Their Role in Health and Disease
• Role of Proximal Tubules in the Pathogenesis of Kidney Disease
• Kidney Microvasculature in Health and Disease
• Renal Interstitial Fibrosis: A Critical Evaluation of the Origin of Myofibroblasts
• Immunopathogenesis of Idiopathic Nephrotic Syndrome
• Membranous Nephropathy
• Prospects and Perspectives on IgA Nephropathy from Animal Models
• Infection-Related Glomerulonephritis
• Discovery of Genes Related to Diabetic Nephropathy in Various Animal Models by Current Techniques
• Glomerular Basement Membrane Disorders in Experimental Models for Renal Diseases: Impact on Understanding Pathogenesis and Improving Diagnosis
• Experimental Models of Lupus Nephritis
• Experimental Models of Membranoproliferative Glomerulonephritis, Including Dense Deposit Disease
• Experimental Models of Vasculitis and Glomerulonephritis Induced by Antineutrophil Cytoplasmic Autoantibodies
• Monoclonal Immunoglobulin Light and Heavy Chain Deposition Diseases: Molecular Models of Common Renal Diseases
• Renal Amyloidosis: Current Views on Pathogenesis and Impact on Diagnosis
• Toward Understanding Renal Fanconi Syndrome: Step by Step Advances through Experimental Models
• Light Chain-Mediated Tubulopathies
• HIV-Associated Nephropathy: Experimental Models
• Acute Kidney Injury: Lessons from Experimental Models
• Pathogenesis of Tubular Interstitial Nephritis
• Obstructive Uropathy
• Renal Vasculature in Essential Hypertension: A Review of Some Contrarian Evidence
• Thrombotic Microangiopathies: From Animal Models to Human Disease and Cure
• Glomerular Repair: Present Status and Future Expectations
• Author Index
• Subject Index