Current Molecular Medicine
Volume 5, Number 5, 2005
Contents
Diseases
of the Kidney: Molecular Mechanisms and Current Therapy
Executive
Editor: Stephen I-Hong Hsu
Editorial Pp.453-454
Stephen
I-Hong Hsu
New Developments in the Field of Cystic
Kidney Diseases Pp.455-465
Ralph
Witzgall
Cellular and Molecular Pathways that Lead to
Progression and Regression of Renal Fibrogenesis Pp.467-474
Hirokazu
Okada and Raghu Kalluri
Molecular Basis of IgA Nephropathy Pp.475-487
Andrew
S.H. Lai and Kar Neng Lai
Bone and the Kidney: A Systems Biology
Approach to the Molecular Mechanisms of Renal Osteodystrophy Pp.489-496
Adrian
Mondry, Zhengyuan Wang and Pawan K. Dhar
Genetic and Genomic Approaches to
Glomerulosclerosis
Pp.497-507
A.
Padiyar and J.R. Sedor
Molecular Genetic Approaches for Studying the
Etiology of Diabetic Nephropathy Pp.509-525
D.P.K.
Ng and A.S. Krolewski
Conditional Gene Targeting in the Kidney Pp.527-536
Alexander
Gawlik and Susan E. Quaggin
Novel Non-rodent Models of Kidney Disease Pp.537-546
Dirk
M. Hentschel and Joseph V. Bonventre
Abstracts
[Back to top] Editorial
Stephen
I-Hong Hsu
The pandemic of
kidney disease in the 21st century affects increasing numbers of individuals and
is associated with significant morbidity and mortality as well as a heavy
economic burden. It has been long predicted that this pandemic will wreck its
greatest havoc in highly populated developing nations such as China and India,
along with the remainder of Asia/Southeast Asia, where the incidence of type 2
diabetes mellitus is on the rise. Clearly, as a world wide clinical and
research community, nephrology is in a state of emergency. Something must be
done—and soon.
Although we
continue to be challenged by our incomplete understanding of the molecular
pathophysiology of acute and chronic renal diseases, including genetic diseases
involving the kidney, it is safe to say that there has never been a more
exciting or important time to be a “molecular nephrologist.” Historically, it
may be argued that nephrology, as a scientific discipline, has been slower than
its sister disciplines such as cardiology and endocrinology, to adopt both the
conceptual and technical approaches and platforms offered by the revolution in
molecular biology begun in the early 80’s. Apologetics notwithstanding, the
stunning success of renal anatomists and physiologists during the
“pre-molecular” era, and which continues to this day, may have contributed to
the prolonged pregnancy and delayed birth of modern molecular nephrology. If
this is indeed the case, then the contents of this volume of current
reviews—representing only a small but representative sampling of the activity
of a dedicated and exceptionally gifted community of modern molecular
nephrologists engaged in a broad spectrum of scientific activities—are a
testament to the coming-of-age of molecular nephrology in the post-genomic era.
It is perhaps
worth considering for a moment the value of the category of the review article
and its function in science. At minimum, review articles succinctly catalogue
the latest developments in a specialized area of investigation, often directly
or indirectly helping the reader to appreciate areas of controversy or pointing
out a critically important gap in knowledge that has been inadvertently
ignored. At its best, a review article may stand as a genuine contribution to
the body of published primary data, when the author is able to offer a new
direction or propose a novel theory or model based on a synthesis of published
data. In this manner and only judged in retrospect, a review article may prove
to be highly influential. Although the authors of the reviews in this volume
were simply instructed to name any topic and any title of their own choosing,
and despite the obvious differences in the styles adopted, it is enormously
gratifying to find that each has produced a review article that may be
acknowledged as having achieved a level of the very highest order.
What better
example of the above than Witzgall’s review of cystic kidney disease? After
managing to concisely cover important new developments and insights arising
from the study of a rather broad category of diseases, he shows us how the
application of molecular methods has unexpectedly uncovered a common theme (the
role of the primary cilium at the apical membrane of renal tubular epithelial
cells) and has brought us to refocus attention on a fundamental and unsolved
problem in basic cell biology research—the “problem of geometry.” He speculates
that primary cilia and their associated proteins play a role in determining
proper tubular geometry. Similarly, Okada and Kalluri emphasize the importance
of delineating the molecular pathways of fibrogenesis that underlie progressive
chronic kidney disease (CKD)—a common clinical outcome irrespective of the
primary injury or disease process. They speculate that genomic approaches hold
the promise for revealing new therapeutic targets that will lead to novel
strategies to prevent and/or reverse renal fibrosis. Lai and Lai provide a
highly comprehensive review of a large body of work related to the molecular
characterization of the immunopathogenesis of a fascinating and elusive
disease, IgA nephropathy, the most common primary glomerulonephritis worldwide
for which no widely accepted therapy or non-invasive diagnostic test is
currently available. They highlight a series of important recent and novel
findings upon which rational therapeutic strategies can begin to be designed
and implemented. The first section is rounded out by a review of the syndrome
of renal osteodystrophy that logically argues in favor of the appropriateness
of a novel systems biology approach towards a more dynamic and quantitative
understanding of the physiology and pathophysiology of renal bone disease.
While the first
section can be loosely labeled as “disease-centric,” the second section
highlights the availability and proper application of powerful molecular
genetic approaches to elucidating molecular pathogenesis in both human and
animal models. This is done in the context of a particular disease or disease
process. Padiyar and Sedor take us through recent studies of familial focal
segmental glomerulosclerosis to demonstrate how genetic and genomic approaches
such as linkage analysis that have led to the identification of mutations in
protein components of the slit diaphragm in rare causes of glomerulosclerosis
(known collectively as podocytopathies), have led to novel insights regarding
the general function of the slit diaphragm in health and disease. The authors
should be complimented for their clearly stated assessment of the dismal state
of population-based genetic association studies of candidate genes for CKD. The
review by Ng and Krolewski reiterates the paradigm of molecular genetic
approaches for identifying genetic variants that make strong (linkage analysis)
and modest or weak (association studies) contributions to the phenotype of
diabetic nephropathy. Importantly, they build on this paradigm by demonstrating
the relative advantages of population- versus family-based association studies,
and by emphasizing the potential synergy between human and experimental animal
approaches (predominantly in mouse). They provide excellent examples of
well-designed linkage and association studies that are ideally suited to serve
as templates for the investigator who would venture into the potentially
treacherous waters of molecular genetic studies. These two reviews provide a
natural segue to the last two reviews that focus on powerful non-human
experimental models for the study of kidney disease and normal renal
physiology. Gawlik and Quaggin provide a highly readable, authoritative and
up-to-date review of conditional gene targeting in the kidney, illustrating the
newly available tools for achieving both spatial and temporal control of gene
expression in the mouse. Recently published techniques for tissue-specific gene
knockdown using RNA interference, which can theoretically be applied in a
genome-wide, high throughput and cost effective manner, as well as a discussion
of evolving forward genetic techniques such as random mutagenesis in mice, are
also covered. It is clear that a tissue-specific conditional gene knockout in
mouse will become a widely applied gold standard for defining the function of a
specific gene. Hentschel and Bonventre provide the first published journal
review of novel non-rodent models for the study of kidney disease, emphasizing
the advantage of non-rodent genetic models for which the entire sequence of the
genome has been determined. They nicely contrast the relative advantages of
studying small organisms in which large scale screening approaches are feasible
and cost-effective, as compared to larger mammals in which physiological and
pathophysiological responses more closely mimic that of humans (especially
useful in transplantation immunology studies). They also provide the images
that grace the cover of this special issue of Current Molecular Medicine,
which are taken from a recently published novel zebrafish model of acute renal
failure.
I wish to thank
the authors for the generous gift of their contribution of time and expertise,
without which this issue would not have been possible. Special thanks to Anil
Mukherjee (Editor-in-Chief) for granting me carte blanche on this project.
Happy reading!
[Back to top] New Developments in the Field of Cystic
Kidney Diseases
Ralph
Witzgall
For quite some
time the field of polycystic kidney disease has led a life at the fringe of
kidney research, but with the cloning of the PKD1 and many other genes
this situation has dramatically changed. Polycystic kidney disease often is a
syndromic disease affecting a variety of organs in addition to the kidney. Most
of the proteins involved in polycystic kidney disease have been localized to
the primary cilium, an extension at the apical membrane of renal tubular
epithelial cells, which may serve chemo- and mechanosensory functions. It is
speculated that primary cilia and their associated proteins play a role in
determining the proper tubular geometry.
[Back to top] Cellular and Molecular Pathways that Lead to
Progression and Regression of Renal Fibrogenesis
Hirokazu
Okada and Raghu Kalluri
Renal fibrosis is a
common consequence and often a central feature of all the progressive renal
diseases that lead to end-stage renal failure. In comparison to wound healing,
during kidney fibrosis the length of the post-inflammatory phase often exceeds
and continues unchecked resulting in scar formation. Infiltrating immune cells
and a heterogeneous colony of interstitial cells derived from a variety of
cellular origins such as resident mesenchymal cells, tubular epithelial cells,
circulating fibrocytes, and bone marrow derived stem cells, communicate with
each other and with inflamed and surviving parenchymal cells via a network of
cytokines and adhesion molecules to populate the renal tubulointerstitial space
during early fibrogenesis. Such fibroblasts subsequently secrete abundant
extracellular matrix to achieve architectural remodeling in parallel with
functional deterioration. Renal fibrosis is a dominant determinant of the
clinical outcome of patients and yet for the most part, current therapies are
ineffective or only marginally effective. This review highlights recent
advances in our understanding of the cellular and molecular events leading to
the progression of renal fibrosis.
[Back to top] Molecular Basis of IgA Nephropathy
Andrew
S.H. Lai and Kar Neng Lai
IgA nephropathy
(IgAN) is the most common glomerulonephritis worldwide and remains an important
cause of end-stage renal failure. However, the basic molecular mechanism(s)
underlying abnormal IgA synthesis, selective mesangial deposition with ensuing
mesangial cell proliferation and extracellular matrix expansion remains poorly
understood. Notably, the severity of tubulointerstitial lesions better predicts
the renal progression than the degree of glomerular lesions. The task of elucidating
the molecular basis of IgAN is made especially challenging by the fact that
both environmental and genetic components likely contribute to the development
and progression of IgAN. This review will summarize the earlier works on the
structure of the IgA molecule, mechanisms of mesangial IgA deposition and
pathophysiologic effects of IgA on mesangial cells following mesangial
deposition. Recently, a series of important advances in the area of
communication between the glomerular mesangium and renal tubular cells have
emerged. These novel findings regarding the molecular pathogenesis of IgAN will
be helpful in designing future directions for therapy.
[Back to top] Bone and the Kidney: A Systems Biology
Approach to the Molecular Mechanisms of Renal Osteodystrophy
Adrian Mondry, Zhengyuan Wang and Pawan K. Dhar
Despite its
apparent static condition, the skeleton undergoes a permanent process of
remodeling mediated by osteoblasts and osteoclasts. The activity of these cells
is regulated by a plethora of factors, ranging from mechanical stress to the
effects of hormones to the immune system. One well-studied regulatory system
involves the maintenance of calcium homeostasis through a network whose main
regulatory components include ionized calcium, phosphate, parathyroid hormone
and active vitamin D. This system establishes the link between bone and kidney,
as one of the kidney’s endocrine functions is the activation of vitamin D,
while electrolyte homeostasis is one of its excretory functions. Impaired renal
function leads to disturbances in this regulatory system, resulting in the
complex syndrome of renal osteodystrophy that affects the majority of patients
with chronic renal failure. This review summarizes the current understanding of
bone physiology on a molecular level, examines some of the pathological
pathways related to renal disease, and concludes with an outlook on how the
emerging field of systems biology may contribute to a more dynamic and
quantitative understanding of the physiology and pathophysiology of renal bone
disease.
[Back to top] Genetic and Genomic Approaches to
Glomerulosclerosis
A.
Padiyar and J.R. Sedor
Chronic kidney
disease (CKD) is common, progressive and expensive to manage. Although
modifiable risk factors can be treated and outcomes improved, CKD remains a
chronic disease with excessive morbidity and mortality. The completion of the
human genome sequence and the advent of methodologies to define gene function
provide new opportunities to manage and treat patients with CKD and other
chronic diseases. Despite the lack of clear correspondence between genotype and
phenotype and an obvious Mendelian inheritance pattern, CKD susceptibility has
a genetic basis. In this review, we focus on recent studies of familial focal
segmental glomerulosclerosis and the discoveries that have resulted from both
genetic and genomic approaches used to understand its pathogenesis. Key slit
diaphragm proteins were discovered using linkage analyses of these rare causes
of glomerulosclerosis and subsequent work has characterized slit diaphragm
function in health and disease. Podocyte dysfunction is now recognized as a key
contributor to the functional and histologic derangements that characterize
glomerular dysfunction in many common causes of CKD. In aggregate, these
studies provide a paradigm for approaches to better define mechanisms of CKD
and to identify novel therapeutic targets.
[Back to top] Molecular Genetic Approaches for Studying the
Etiology of Diabetic Nephropathy
D.P.K.
Ng and A.S. Krolewski
A critical
challenge faced by clinical nephrologists today is the escalating number of
patients developing end stage renal disease, a major proportion of which is
attributed to diabetic nephropathy (DN). The need for new measures to prevent
and treat this disease cannot be overemphasized. To this end, modern genetic
approaches provide powerful tools to investigate the etiology of DN. Human
studies have already established the importance of genetic susceptibility for
DN. Several major susceptibility loci have been identified using linkage
studies. In addition, linkage studies in rodents have pinpointed promising
chromosomal segments that influence renal traits. Besides augmenting our
understanding of disease pathogenesis, these animal studies may facilitate the
cloning of disease susceptibility genes in man through the identification of
homologous regions that contribute to renal disease. In human diabetes, various
genes have been evaluated for their risk contribution to DN. This widespread
strategy has been propelled by our knowledge of the glucose-activated pathways
underlying DN. Evidence has emerged that a true association does indeed exist
for some candidate genes. Furthermore, the in vivo manipulation of gene
expression has shown that these genes can modify features of DN in transgenic
and knockout rodent models, thus corroborating the findings from human
association studies. Still, the exact molecular mechanisms involving these
genes remain to be fully elucidated. This formidable task may be accomplished
by continuing to harness the synergy between human and experimental genetic
approaches. In this respect, our review provides a first synthesis of the
current literature to facilitate this challenging effort.
[Back to top] Conditional Gene Targeting in the Kidney
Alexander
Gawlik and Susan E. Quaggin
Complete mapping of
the genome in a number of organisms provides a challenge for experimental
nephrologists to identify potential functions of a vast number of new genes in
the kidney. Since knockout technologies have evolved in the early eighties the
mouse has become a valuable model organism. Researchers can now artificially
eliminate the expression of specific genes in a mammalian organism and examine
the phenotype. New developments have emerged that allow investigators to knock
out a gene specifically in the kidney. Several kidney-specific promoters
provide valuable tools and bacterial artificial chromosome (BAC) based
techniques like recombineering will enhance both number and accuracy of new
mouse lines with spatially controlled gene expression. In addition to spatial control,
tetracycline- or tamoxifen-inducible systems, provide the possibility of
influencing the temporal expression pattern of a gene enabling researchers to
dissect its functions in adult organisms. Knocking out a gene will continue to
be the gold standard for defining the role of a specific gene whereas
tissue-specific gene knockdown using RNA interference represents an alternative
approach for generating lower-priced and fast loss of function models. In
addition to reverse genetic approaches, forward genetic techniques like random
mutagenesis in mice continue to evolve and will enhance our understanding of
disease mechanisms in the kidney.
[Back to top] Novel Non-rodent Models of Kidney Disease
Kidney disease in
the 21st century affects increasing numbers of individuals. We
continue to be challenged by our lack of understanding of the pathophysiology
of acute and chronic renal disease including genetic diseases involving the
kidney. Rodent knockout animals or inbred strains have greatly contributed to
our understanding of many monogenetic and complex diseases. Non-rodent animal
models of disease have become more attractive since genomic data has become
available for a variety of organisms that offer distinct advantages over mice
and rats for ease in conducting high-throughput chemical or mutagenesis
screens. It is thus timely to examine the physiology and pathophysiology of the
kidney or kidney equivalents in these organisms to evaluate their relevance as
models for human disease. In addition to organisms whose small size and
accessibility facilitate large scale screening approaches, larger animals at
the other end of the spectrum offer unique physiological advantages in both
size equivalency to humans as well as, in some cases, physiological and
pathophysiological responses that closely mimic those of humans. Here we review
a selected number of non-rodent experimental models of kidney diseases,
focusing on recent advances in the use of the worm Caenorhabditis elegans,
the fruitfly Drosophila melanogaster, the zebrafish Danio rerio,
the little skate Leucoraja erinacea, the MGH miniature swine, merino
cross sheep, and the cow Bos taurus to study kidney disease.