- Email: [email protected]
Animal models of renal disease
Drug Discovery Today: Disease Models
DRUG DISCOVERY
TODAY
DISEASE
MODELS
Vol. 11, 2014
Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Andrew McCulloch – University of California, SanDiego, USA
Animal models of renal disease
EDITORIAL
Animal models of renal disease Charles E. Alpers Department of Pathology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356100, Room NE110, Seattle, WA 98195, USA. Email: ([email protected])
The value of animal models for studies of the pathogenesis and natural history of kidney disease is beyond question. Recreating the complexity of mammalian organ structure and function, as well as the perturbations which lead to organ-specific or systemic diseases, cannot be adequately captured in more limited and somewhat artificial systems such as cell culture or in silico settings. Animal models allow us to envision how perturbations in metabolism or host exposure to external pathogenic stimuli such as microbes or other elements of a hostile environment lead to disease or modified expression of disease. An ideal animal model of any specific disease category would reproduce most or all of the lesions of the human disease and would be susceptible to genetic analysis. For practical reasons such an animal model should be cheap to maintain and be widely available. These last requirements generally preclude consideration of nonhuman primates, dogs, and swine as widely utilizable animal species for model development. Although there are examples where investigators have used lower order model systems such as fruit flies and zebrafish to gain mechanistic insights into renal injury, the greatest amount of information on renal diseases available comes from mammalian models, and this is reflected in the discussion of relevant disease models in this compilation of reviews. The focus is largely on rodent (mouse and rat) disease models, for reasons that include their wide availability, their low cost relative to higher order mammals, and the technological ease with which genetic mutations can be introduced, that allow cell fate tracking and testing of specific molecules as mediators of disease. There are a multitude of animal model systems to study kidney development, and genetic and congenital disease such as polycystic kidney, immune mediated diseases, acute 1740-6757/$ ß 2014 Elsevier Ltd. All rights reserved.
toxic and ischemic injuries, progressively fibrotic injuries, and aging. In this set of reviews, leading animal models of specific classes of disease (IgA nephropathy, lupus nephritis) and common pathways that determine clinical and structural manifestations and outcome of diseases of the kidney arising
Charles Alpers is a Professor of Pathology and Adjunct Professor of Medicine at the University of Washington, Seattle, WA, USA, where he also serves as Vice-Chair of Pathology. At the University of Washington, he directs a large renal biopsy pathology service, and his research interests are focused on models of diabetic nephropathy and mechanisms that promote progressive glomerular injury in experimental models of glomerulonephritis. He received his undergraduate education at Yale University, and his M.D. degree from the University of Rochester in 1978. His postgraduate training included two years of training in internal medicine at Boston University, four years of training in anatomic and clinical pathology at the University of California, San Francisco, and two years of clinical and research training at the Brigham and Women’s Hospital in Boston, before he assumed a faculty position at the University of Washington in 1986. He has served as councilor and president of the Renal Pathology Society. Recently, he has been the founding chair of the Glomerular Disease Advisory Group of the American Society of Nephrology, and has co-organized and co-directed the courses in renal pathology at the World Congress of Nephrology meetings in 2007, 2009, 2011, and 2013. He has authored or coauthored 266 original research papers, 34 review/editorial articles, and 33 book chapters, and is co-author of the textbook Fundamentals of Renal Pathology (2014).
http://dx.doi.org/10.1016/j.ddmod.2014.12.003
1
Drug Discovery Today: Disease Models | Animal models of renal disease
from a multiplicity of inciting events (inflammatory injury, dysregulation of complement) and disease evolution (integrins in injury and repair, pathways of progressive renal injury) will be presented and compared. The goal is to provide a comprehensive and useful guide to currently available model systems for investigators seeking relevant models that can be used to identify and test therapeutic targets that will be clinically relevant to kidney disease patients. In these considerations of animal models of disease, we should keep in mind those features that model initiation of disease, that focus on mediators that influence chronology and severity of onset and influence progression, and focus on factors that influence repair. In this regard, we call particular attention to a consideration that is a central point of each of the following reviews: What are the features of a human disease or the injury processes that determine the manifestations of this disease that should be present in an animal model of the disease, and to what extent are they indeed present? The answers to these questions ultimately determines the potential of a given animal model to yield translational insights from basic biologic research, and its value for testing the therapeutic efficacy of new drug regimens. The absolute limitations of animal models are also a crucial issue that is addressed in these reviews. Even if we restrict consideration of disease models to mammalian systems, we have learned that use of inbred mouse strains can result in limited reproducibility of pathogenic stimuli and disease manifestations from one strain to another. Certain inbred strains are particularly suited to the introduction of genetic mutations that are powerful tools for analysis of pathophysiologic events. However, the different susceptibilities of mouse strains for specific diseases (a noteworthy example is the conclusion of the Animal Models of Diabetes Complication Consortium than mice of the C57Bl/6 strain are particularly resistant to developing the structural alterations characteristic of diabetic nephropathy [1]) can severely limit the generalizability of studies in one strain to the more complex, outbred human condition. Accordingly, as the preponderance of mouse mutations are introduced and propagated in C57Bl/6, FVB, and 129S strains, there can be substantial further limits to reproducibility and generalizability of key findings when only a limited number of strains with these mutations can be studied. This important issue is not a principal focus of the invited reviews, but nonetheless must be kept in mind in assessing the utility of any animal model of disease. The first review in this series, by Suzuki et al., focuses on IgA nephropathy, widely acknowledged to be the commonest form of glomerulonephritis encountered worldwide. Major advances in our understanding of the pathogenesis of this disorder have come from the laboratory of Jan Novak, one of the authors of this review. These particular studies have identified the role of aberrant glycosylation of IgA molecules, 2
www.drugdiscoverytoday.com
Vol. 11, 2014
which then may become an antigenic target of autoantibodies leading to immune complex formation and deposition in the kidney glomeruli. This then incites a series of acute or chronic inflammatory and/or fibrosing sclerosing injuries, which necessarily involve some of the disease pathways considered in the reviews by Holderied et al., Zent et al. and Lim et al. on inflammation, integrins, matrix, and disease progression. Development of model systems of IgA nephropathy that closely mimic the human disease has proven to be especially challenging. Suzuki et al. point out that only humans and nonhuman primates have an antibody repertoire that includes the IgA1 subclass which is the pathogenic antibody of IgA nephropathy; this has been a major barrier to developing a useful model of this disease. Undeterred by this obstacle, they detail how a spontaneous model of IgA deposition in the ddY mouse strain was modified through a lengthy breeding/phenotyping program to develop a mouse model with a predictable disease course, from which genetic susceptibility data could be obtained and from which studies of aberrant glycosylation could be performed. Their studies lead to a conclusion that while rodent models cannot recapitulate some key aspects of IgA nephropathy without substantial genetic manipulation, they can be enhanced to model enough key aspects that they can be useful for studies of those additional aspects that contribute to disease. These additional attributes, when identified, can be used for preclinical identification of new therapeutic targets. Animal models of systemic lupus, and specifically of lupus nephritis, have been studied for several decades. Such models are complex, as lupus nephritis is the result of pathogenetic events that take place both in the kidney and systemically. Therefore, the utility of animal models that inform us of pathophysiologic mechanisms, and identify new therapeutic targets, will depend in part on the ability of such models to encompass both systemic and kidney-specific mechanisms of disease, and recognize that unique and valuable opportunities for kidney therapeutics may come from targeting disease pathways occurring outside the kidney. McGaha and Madaio review the very complex interactions of immune dysregulation and engagement of inflammatory pathways that converge in the development of lupus nephritis in humans. They focus on the development of an immune complex deposition process in the kidney, and the development of systemic autoimmunity and subsequent inflammatory events within the kidney. They provide a cogent description of the leading genetic and inducible rodent models of lupus, and review some of the key genetic mutations in immune pathways identified in rodent models that have been the basis of current paradigms of lupus nephritis pathogenesis. A particularly valuable component of their review is a comparison of clinical, histologic, and immunologic features
Vol. 11, 2014
of the leading rodent models of lupus nephritis, and the degree to which they model specific features of proliferative forms of lupus nephritis (categories Class III and Class IV of the current International Society of Nephrology/Renal Pathology Society classification of human lupus nephritis [2]. These are the classes of lupus nephritis which cause the greatest acute renal impairment, have inflammatory lesions that are the most amenable to current therapeutics, and, if unsuccessfully treated, have the greatest potential for subsequent renal scarring. Understanding the most relevant features of lupus nephritis models and where they may fall short of modeling features of proliferative lupus nephritis may facilitate successful preclinical studies that block or modify specific elements of the autoimmune and inflammatory responses. These include the influx of specific classes of inflammatory (or reparative) cells into the sites of kidney injury, in situ formation and disposal of immune complexes, and downstream events leading to either progressive renal injury or resolution. Animal models of the less inflammatory and progressive forms of lupus nephritis (mesangial proliferative lupus nephritis, ISN/RPS Classes I and II, and membranous lupus nephritis, ISN/RPS Class V) have not been as widely studied or characterized, in accord with the clinical experience that these classes of lupus nephritis are likely to have a relatively ‘benign’ outcome. Accordingly, these disease classes have not been targets for therapeutic regimens directed to the manifestations of systemic lupus, and the need for good animal models of these processes is less imperative. In turning to models of processes of renal injury rather than specific disease types, Alexander Holderied and HansJoachim Anders first identify the parameters that must be considered in choosing appropriate animal models for translational studies of inflammatory injury of the kidney. They cover in great breadth the range of rodent models that have been employed to model specific types of inflammatory injury to glomeruli and the tubulointerstitium. The range of injuries surveyed include immune complex deposition, renal infection, renal ischemia, renal exposure to toxins, and renal allograft rejection. Barbour et al. offer a very concise summary of a fairly recent and still emerging understanding of diseases resulting from dysregulation of the alternate pathway of complement activation. Very precise characterization of molecular alterations in components of this pathway has led to re-evaluation of what had been well characterized patterns of glomerular injury in humans (membranoproliferative glomerulonephritis, postinfectious glomerulonephritis), some with well-established etiologies and some without, and led to the recent recognition of a new category of renal disease termed C3 glomerulopathy. An extraordinary development has been the characterization of mutations in this same pathway that lead to a seemingly disparate disease process of atypical hemolytic uremic syndrome. The authors show
Drug Discovery Today: Disease Models | Animal models of renal disease
studies of Cfh / (complement factor H) mice, Cfb (complement factor B) deficient mice, and mice with other mutations in complement pathway molecules, largely performed in their laboratories, can develop progressive glomerulonephritis with similarities to dense deposit disease (an entity now recognized as one type of C3 glomerulopathy), while an alternate mutation in complement factor H can produce structural changes of thrombotic microangiopathy analogous to those encountered in human atypical hemolytic syndrome. These and a multitude of other observations detailed in their review are extremely illuminating findings that have provided murine models to test therapeutics for thrombotic microangiopathy occurring in the context of human antiphospholipid antibody syndromes, and have provided preclinical platforms for testing complement based therapeutics such as the C5 inhibitor eculizumab, now in clinical use for atypical hemolytic uremic syndrome. This review also covers recent advances in understanding complement mediation of lupus nephritis, a process directly consequent to the immune complex deposition processes discussed in both the reviews of McGaha et al. and Holderied et al. Studies of the Clqa / mouse and of other pathways which regulate leukocyte recruitment and engagement provide crucial insight into complement mediation of lupus nephritis, although the information gained to date from the models cited has left unresolved the degree to which lupus nephritis is mediated by complement activation. The use of animal models to study the role of basement membrane matrix and integrins in renal disease has been a long standing focus of both Ambra Pozzi and Roy Zent. Their studies have elucidated elements of cell–matrix interactions crucial to normal renal development and maintenance of healthy kidneys, and in their review they provide a detailed consideration of the collagen 4A3 subunit (COL4A3) null mouse, an increasingly used mouse model of the human hereditary basement membrane disorder of Alport syndrome, but also an increasingly used model of fibrosing renal tubulointestintial injury. They provide unique insights into laminin binding integrins such as alpha3beta1 that are needed to maintain podocyte attachment to the glomerular basement membrane, and how disruption of these attachments can lead to glomerular diseases such as focal and segmental glomerulosclerosis. Very importantly, they survey a large body of work that establishes binding relationships of TGFb latency associated peptide to multiple integrin classes, and how targeting certain integrin subunits can be protective of fibrosing injury in some renal diseases. The final review in this series by Beom Jin Lim, Hai-Chun Yang, and Agnes Fogo is a comprehensive survey of models of renal fibrosis. A principle adverse outcome common to kidney diseases in general is the development of fibrosis as the structural correlate of progressive CKD. Interruption of fibrosis remains a major challenge for pharmaceutical companies www.drugdiscoverytoday.com
3
Drug Discovery Today: Disease Models | Animal models of renal disease
and academic investigators alike. Perhaps the most well characterized target for amelioration of progressive fibrosing renal disease has been TGF-b. At the recent annual meeting of the American Society of Nephrology, a somewhat disappointing result was reported from a clinical trial to test efficacy of an anti-TGF-b antibody to slow or prevent disease progression in patients with diabetic nephropathy (Voelker JR, et al. Renal efficacy and safety of anti-TGF-b1 therapy in patients with diabetic nephropathy. Presented at the annual meeting of the American Society of Nephrology. Philadelphia, PA; November 2014). While details of this study await full publication and further analysis, the review of Lim, Yang, and Fogo suggests multiple additional pathways that have promise for regression of established renal disease. Their review illustrates some of the opportunities afforded by progressive injury models of both spontaneous origin (e.g. the MWF rat, the spontaneously hypertensive rat, and aging) and induced (puromycin aminonucleoside nephrosis, 5/6 nephrectomy, diabetes) to identify key pathways amenable to interventions that may stabilize or regress chronic structural injury.
4
www.drugdiscoverytoday.com
Vol. 11, 2014
In aggregate, the reviews have focused on acute and progressive disease involving the glomerular and tubulointerstitial compartments of the kidney. In humans, the contribution of injuries to the microvasculature and a major functional consequence of such injury, hypertension, is a well-recognized component of progressive kidney disease. It must be pointed out that corresponding good rodent models or model systems using lower order organisms that recapitulate changes to the microvasculature readily found in human disease have not been easy to identify or create. These are among the challenges that remain for further model development of kidney disease.
References [1] Brosius 3rd FC, Alpers CE, Bottinger EP, Breyer MD, Coffman TM, Gurley SB, et al. Mouse models of diabetic nephropathy. J Am Soc Nephrol 2009;20:2503–12. [2] Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521–30; Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241–50.
DRUG DISCOVERY
TODAY
DISEASE
MODELS
Vol. 11, 2014
Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Andrew McCulloch – University of California, SanDiego, USA
Animal models of renal disease
EDITORIAL
Animal models of renal disease Charles E. Alpers Department of Pathology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356100, Room NE110, Seattle, WA 98195, USA. Email: ([email protected])
The value of animal models for studies of the pathogenesis and natural history of kidney disease is beyond question. Recreating the complexity of mammalian organ structure and function, as well as the perturbations which lead to organ-specific or systemic diseases, cannot be adequately captured in more limited and somewhat artificial systems such as cell culture or in silico settings. Animal models allow us to envision how perturbations in metabolism or host exposure to external pathogenic stimuli such as microbes or other elements of a hostile environment lead to disease or modified expression of disease. An ideal animal model of any specific disease category would reproduce most or all of the lesions of the human disease and would be susceptible to genetic analysis. For practical reasons such an animal model should be cheap to maintain and be widely available. These last requirements generally preclude consideration of nonhuman primates, dogs, and swine as widely utilizable animal species for model development. Although there are examples where investigators have used lower order model systems such as fruit flies and zebrafish to gain mechanistic insights into renal injury, the greatest amount of information on renal diseases available comes from mammalian models, and this is reflected in the discussion of relevant disease models in this compilation of reviews. The focus is largely on rodent (mouse and rat) disease models, for reasons that include their wide availability, their low cost relative to higher order mammals, and the technological ease with which genetic mutations can be introduced, that allow cell fate tracking and testing of specific molecules as mediators of disease. There are a multitude of animal model systems to study kidney development, and genetic and congenital disease such as polycystic kidney, immune mediated diseases, acute 1740-6757/$ ß 2014 Elsevier Ltd. All rights reserved.
toxic and ischemic injuries, progressively fibrotic injuries, and aging. In this set of reviews, leading animal models of specific classes of disease (IgA nephropathy, lupus nephritis) and common pathways that determine clinical and structural manifestations and outcome of diseases of the kidney arising
Charles Alpers is a Professor of Pathology and Adjunct Professor of Medicine at the University of Washington, Seattle, WA, USA, where he also serves as Vice-Chair of Pathology. At the University of Washington, he directs a large renal biopsy pathology service, and his research interests are focused on models of diabetic nephropathy and mechanisms that promote progressive glomerular injury in experimental models of glomerulonephritis. He received his undergraduate education at Yale University, and his M.D. degree from the University of Rochester in 1978. His postgraduate training included two years of training in internal medicine at Boston University, four years of training in anatomic and clinical pathology at the University of California, San Francisco, and two years of clinical and research training at the Brigham and Women’s Hospital in Boston, before he assumed a faculty position at the University of Washington in 1986. He has served as councilor and president of the Renal Pathology Society. Recently, he has been the founding chair of the Glomerular Disease Advisory Group of the American Society of Nephrology, and has co-organized and co-directed the courses in renal pathology at the World Congress of Nephrology meetings in 2007, 2009, 2011, and 2013. He has authored or coauthored 266 original research papers, 34 review/editorial articles, and 33 book chapters, and is co-author of the textbook Fundamentals of Renal Pathology (2014).
http://dx.doi.org/10.1016/j.ddmod.2014.12.003
1
Drug Discovery Today: Disease Models | Animal models of renal disease
from a multiplicity of inciting events (inflammatory injury, dysregulation of complement) and disease evolution (integrins in injury and repair, pathways of progressive renal injury) will be presented and compared. The goal is to provide a comprehensive and useful guide to currently available model systems for investigators seeking relevant models that can be used to identify and test therapeutic targets that will be clinically relevant to kidney disease patients. In these considerations of animal models of disease, we should keep in mind those features that model initiation of disease, that focus on mediators that influence chronology and severity of onset and influence progression, and focus on factors that influence repair. In this regard, we call particular attention to a consideration that is a central point of each of the following reviews: What are the features of a human disease or the injury processes that determine the manifestations of this disease that should be present in an animal model of the disease, and to what extent are they indeed present? The answers to these questions ultimately determines the potential of a given animal model to yield translational insights from basic biologic research, and its value for testing the therapeutic efficacy of new drug regimens. The absolute limitations of animal models are also a crucial issue that is addressed in these reviews. Even if we restrict consideration of disease models to mammalian systems, we have learned that use of inbred mouse strains can result in limited reproducibility of pathogenic stimuli and disease manifestations from one strain to another. Certain inbred strains are particularly suited to the introduction of genetic mutations that are powerful tools for analysis of pathophysiologic events. However, the different susceptibilities of mouse strains for specific diseases (a noteworthy example is the conclusion of the Animal Models of Diabetes Complication Consortium than mice of the C57Bl/6 strain are particularly resistant to developing the structural alterations characteristic of diabetic nephropathy [1]) can severely limit the generalizability of studies in one strain to the more complex, outbred human condition. Accordingly, as the preponderance of mouse mutations are introduced and propagated in C57Bl/6, FVB, and 129S strains, there can be substantial further limits to reproducibility and generalizability of key findings when only a limited number of strains with these mutations can be studied. This important issue is not a principal focus of the invited reviews, but nonetheless must be kept in mind in assessing the utility of any animal model of disease. The first review in this series, by Suzuki et al., focuses on IgA nephropathy, widely acknowledged to be the commonest form of glomerulonephritis encountered worldwide. Major advances in our understanding of the pathogenesis of this disorder have come from the laboratory of Jan Novak, one of the authors of this review. These particular studies have identified the role of aberrant glycosylation of IgA molecules, 2
www.drugdiscoverytoday.com
Vol. 11, 2014
which then may become an antigenic target of autoantibodies leading to immune complex formation and deposition in the kidney glomeruli. This then incites a series of acute or chronic inflammatory and/or fibrosing sclerosing injuries, which necessarily involve some of the disease pathways considered in the reviews by Holderied et al., Zent et al. and Lim et al. on inflammation, integrins, matrix, and disease progression. Development of model systems of IgA nephropathy that closely mimic the human disease has proven to be especially challenging. Suzuki et al. point out that only humans and nonhuman primates have an antibody repertoire that includes the IgA1 subclass which is the pathogenic antibody of IgA nephropathy; this has been a major barrier to developing a useful model of this disease. Undeterred by this obstacle, they detail how a spontaneous model of IgA deposition in the ddY mouse strain was modified through a lengthy breeding/phenotyping program to develop a mouse model with a predictable disease course, from which genetic susceptibility data could be obtained and from which studies of aberrant glycosylation could be performed. Their studies lead to a conclusion that while rodent models cannot recapitulate some key aspects of IgA nephropathy without substantial genetic manipulation, they can be enhanced to model enough key aspects that they can be useful for studies of those additional aspects that contribute to disease. These additional attributes, when identified, can be used for preclinical identification of new therapeutic targets. Animal models of systemic lupus, and specifically of lupus nephritis, have been studied for several decades. Such models are complex, as lupus nephritis is the result of pathogenetic events that take place both in the kidney and systemically. Therefore, the utility of animal models that inform us of pathophysiologic mechanisms, and identify new therapeutic targets, will depend in part on the ability of such models to encompass both systemic and kidney-specific mechanisms of disease, and recognize that unique and valuable opportunities for kidney therapeutics may come from targeting disease pathways occurring outside the kidney. McGaha and Madaio review the very complex interactions of immune dysregulation and engagement of inflammatory pathways that converge in the development of lupus nephritis in humans. They focus on the development of an immune complex deposition process in the kidney, and the development of systemic autoimmunity and subsequent inflammatory events within the kidney. They provide a cogent description of the leading genetic and inducible rodent models of lupus, and review some of the key genetic mutations in immune pathways identified in rodent models that have been the basis of current paradigms of lupus nephritis pathogenesis. A particularly valuable component of their review is a comparison of clinical, histologic, and immunologic features
Vol. 11, 2014
of the leading rodent models of lupus nephritis, and the degree to which they model specific features of proliferative forms of lupus nephritis (categories Class III and Class IV of the current International Society of Nephrology/Renal Pathology Society classification of human lupus nephritis [2]. These are the classes of lupus nephritis which cause the greatest acute renal impairment, have inflammatory lesions that are the most amenable to current therapeutics, and, if unsuccessfully treated, have the greatest potential for subsequent renal scarring. Understanding the most relevant features of lupus nephritis models and where they may fall short of modeling features of proliferative lupus nephritis may facilitate successful preclinical studies that block or modify specific elements of the autoimmune and inflammatory responses. These include the influx of specific classes of inflammatory (or reparative) cells into the sites of kidney injury, in situ formation and disposal of immune complexes, and downstream events leading to either progressive renal injury or resolution. Animal models of the less inflammatory and progressive forms of lupus nephritis (mesangial proliferative lupus nephritis, ISN/RPS Classes I and II, and membranous lupus nephritis, ISN/RPS Class V) have not been as widely studied or characterized, in accord with the clinical experience that these classes of lupus nephritis are likely to have a relatively ‘benign’ outcome. Accordingly, these disease classes have not been targets for therapeutic regimens directed to the manifestations of systemic lupus, and the need for good animal models of these processes is less imperative. In turning to models of processes of renal injury rather than specific disease types, Alexander Holderied and HansJoachim Anders first identify the parameters that must be considered in choosing appropriate animal models for translational studies of inflammatory injury of the kidney. They cover in great breadth the range of rodent models that have been employed to model specific types of inflammatory injury to glomeruli and the tubulointerstitium. The range of injuries surveyed include immune complex deposition, renal infection, renal ischemia, renal exposure to toxins, and renal allograft rejection. Barbour et al. offer a very concise summary of a fairly recent and still emerging understanding of diseases resulting from dysregulation of the alternate pathway of complement activation. Very precise characterization of molecular alterations in components of this pathway has led to re-evaluation of what had been well characterized patterns of glomerular injury in humans (membranoproliferative glomerulonephritis, postinfectious glomerulonephritis), some with well-established etiologies and some without, and led to the recent recognition of a new category of renal disease termed C3 glomerulopathy. An extraordinary development has been the characterization of mutations in this same pathway that lead to a seemingly disparate disease process of atypical hemolytic uremic syndrome. The authors show
Drug Discovery Today: Disease Models | Animal models of renal disease
studies of Cfh / (complement factor H) mice, Cfb (complement factor B) deficient mice, and mice with other mutations in complement pathway molecules, largely performed in their laboratories, can develop progressive glomerulonephritis with similarities to dense deposit disease (an entity now recognized as one type of C3 glomerulopathy), while an alternate mutation in complement factor H can produce structural changes of thrombotic microangiopathy analogous to those encountered in human atypical hemolytic syndrome. These and a multitude of other observations detailed in their review are extremely illuminating findings that have provided murine models to test therapeutics for thrombotic microangiopathy occurring in the context of human antiphospholipid antibody syndromes, and have provided preclinical platforms for testing complement based therapeutics such as the C5 inhibitor eculizumab, now in clinical use for atypical hemolytic uremic syndrome. This review also covers recent advances in understanding complement mediation of lupus nephritis, a process directly consequent to the immune complex deposition processes discussed in both the reviews of McGaha et al. and Holderied et al. Studies of the Clqa / mouse and of other pathways which regulate leukocyte recruitment and engagement provide crucial insight into complement mediation of lupus nephritis, although the information gained to date from the models cited has left unresolved the degree to which lupus nephritis is mediated by complement activation. The use of animal models to study the role of basement membrane matrix and integrins in renal disease has been a long standing focus of both Ambra Pozzi and Roy Zent. Their studies have elucidated elements of cell–matrix interactions crucial to normal renal development and maintenance of healthy kidneys, and in their review they provide a detailed consideration of the collagen 4A3 subunit (COL4A3) null mouse, an increasingly used mouse model of the human hereditary basement membrane disorder of Alport syndrome, but also an increasingly used model of fibrosing renal tubulointestintial injury. They provide unique insights into laminin binding integrins such as alpha3beta1 that are needed to maintain podocyte attachment to the glomerular basement membrane, and how disruption of these attachments can lead to glomerular diseases such as focal and segmental glomerulosclerosis. Very importantly, they survey a large body of work that establishes binding relationships of TGFb latency associated peptide to multiple integrin classes, and how targeting certain integrin subunits can be protective of fibrosing injury in some renal diseases. The final review in this series by Beom Jin Lim, Hai-Chun Yang, and Agnes Fogo is a comprehensive survey of models of renal fibrosis. A principle adverse outcome common to kidney diseases in general is the development of fibrosis as the structural correlate of progressive CKD. Interruption of fibrosis remains a major challenge for pharmaceutical companies www.drugdiscoverytoday.com
3
Drug Discovery Today: Disease Models | Animal models of renal disease
and academic investigators alike. Perhaps the most well characterized target for amelioration of progressive fibrosing renal disease has been TGF-b. At the recent annual meeting of the American Society of Nephrology, a somewhat disappointing result was reported from a clinical trial to test efficacy of an anti-TGF-b antibody to slow or prevent disease progression in patients with diabetic nephropathy (Voelker JR, et al. Renal efficacy and safety of anti-TGF-b1 therapy in patients with diabetic nephropathy. Presented at the annual meeting of the American Society of Nephrology. Philadelphia, PA; November 2014). While details of this study await full publication and further analysis, the review of Lim, Yang, and Fogo suggests multiple additional pathways that have promise for regression of established renal disease. Their review illustrates some of the opportunities afforded by progressive injury models of both spontaneous origin (e.g. the MWF rat, the spontaneously hypertensive rat, and aging) and induced (puromycin aminonucleoside nephrosis, 5/6 nephrectomy, diabetes) to identify key pathways amenable to interventions that may stabilize or regress chronic structural injury.
4
www.drugdiscoverytoday.com
Vol. 11, 2014
In aggregate, the reviews have focused on acute and progressive disease involving the glomerular and tubulointerstitial compartments of the kidney. In humans, the contribution of injuries to the microvasculature and a major functional consequence of such injury, hypertension, is a well-recognized component of progressive kidney disease. It must be pointed out that corresponding good rodent models or model systems using lower order organisms that recapitulate changes to the microvasculature readily found in human disease have not been easy to identify or create. These are among the challenges that remain for further model development of kidney disease.
References [1] Brosius 3rd FC, Alpers CE, Bottinger EP, Breyer MD, Coffman TM, Gurley SB, et al. Mouse models of diabetic nephropathy. J Am Soc Nephrol 2009;20:2503–12. [2] Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521–30; Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241–50.