Polycystic Kidney Disease

361 Pages·2019·7.903 MB·\361

by  Jinghua Hu (Author), Yong Yu (Author)

Polycystic Kidney Disease Polycystic
This volume focuses on the investigatory methods applied to autosomal
dominant polycystic kidney disease (ADPKD), one of the most common
human genetic diseases. ADPKD is caused by mutations in PKD1 and TRPP2,
Kidney Disease
two integral membrane proteins that function as receptor/ion channels in
primary cilia of tubular epithelial cells. Thus, ADPKD belongs to ciliopathies,
a group of disorders caused by abnormal cilia formation or function. This
book covers the state-of-the-art methods ranging from molecular biology,
biochemistry, electrophysiology, to tools in model animal studies.
Key Features
• Explores the role of cilia in polycystic kidney disease
• Focuses on myriad state-of-the-art methods and techniques
• Reviews specific mutations integral to this autosomal genetic disease
• Includes discussions of model systems
Related Titles
Lim, W. et al. Cell Signaling: Principles and Mechanisms
(ISBN 9780815342441).
Marks, F. et al. Cell Signal Processing: An Introduction to the Molecular
Mechanisms of Signal Transduction (ISBN 9780815345343).
Zhu, M.X., ed. TRP Channels (ISBN 9781138116160).
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Jinghua Hu and Yong Yu
METHODS METHODS IN SIGNAL TRANSDUCTION SERIES
IN SIGNAL TRANSDUCTION
ISBN: 978-1-138-60389-9
90000
9 781138 603899
Polycystic Kidney Disease
Methods in Signal Transduction
Series Editors: Joseph Eichberg Jr. and Michael X. Zhu
The overall theme of this series continues to be the presentation of the wealth of up-to-date research
methods applied to the many facets of signal transduction. Each volume is assembled by one or more
editors who are preeminent in their specialty. In turn, the guiding principle for editors is to recruit chapter
authors who will describe procedures and protocols with which they are intimately familiar in a reader-
friendly format. The intent is to assure that each volume will be of maximum practical value to a broad
audience, including students and researchers just entering an area, as well as seasoned investigators.
Lipid Second Messengers
Suzanne G. Laychock and Ronald P. Rubin
G Proteins: Techniques of Analysis
David R. Manning
Signaling through Cell Adhesion Molecules
Jun-Lin Guan
G Protein-Coupled Receptors
Tatsuya Haga and Gabriel Berstein
G Protein-Coupled Receptors: Structure, Function, and Ligand Screening
Tatsuya Haga and Shigeki Takeda
Calcium Signaling, Second Edition
James W. Putney, Jr.
Analysis of Growth Factor Signaling in Embryos
Malcolm Whitman and Amy K. Sater
Signal Transduction in the Retina
Steven J. Fliesler and Oleg G. Kisselev
Signaling by Toll-Like Receptors
Gregory W. Konat
Lipid-Mediated Signaling
Eric J. Murphy and Thad A. Rosenberger
TRP Channels
Michael Xi Zhu
Cyclic Nucleotide Signaling
Xiaodong Cheng
Gap Junction Channels and Hemichannels
Donglin Bai and Juan C. Sáez
Signaling Mechanisms Regulating T Cell Diversity and Function
Jonathan Soboloff and Dietmar J. Kappes
Lipid-Mediated Signaling Transduction, Second Edition
Eric Murphy, Thad Rosenberger, and Mikhail Golovko
Calcium Entry Channels in Non-Excitable Cells
Juliusz Ashot Kozak and James W. Putney, Jr.
Autophagy and Signaling
Esther Wong
Signal Transduction and Smooth Muscle
Mohamed Trebak and Scott Earley
Polycystic Kidney Disease
Jinghua Hu and Yong Yu
For more information about this series, please visit: https://www.crcpress.com/Methods-in-Signal-
Transduction-Series/book-series/CRCMETSIGTRA?page=&order=pubdate&size=12&view=list&st
atus=published,forthcoming
Polycystic Kidney Disease
Edited by
Jinghua Hu
Department of Biochemistry and Molecular Biology
Mayo Clinic
Rochester, Minnesota
Yong Yu
Department of Biological Sciences
St. John’s University
Queens, New York
Cover image from Kevin Yu, a sophomore at Hunter College High School, New York. From the
amateur but insightful perspective of a young and curious mind, Kevin Yu incorporates many
components in the context of polycystic kidney disease to vividly reflect the endeavor devoted to
curing the disease. In his drawing, we, the scientists, are hard-working birds who are trying their
best to remove cysts from the diseased kidney. We are fortunate to have this image, which projects
our belief that the communication between scientists and laymen, also true for the multidiscipline
interactions among scientists, does not have to be intimidating.
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Contents
Preface......................................................................................................................vii
Editors .......................................................................................................................ix
Contributors ..............................................................................................................xi
Chapter 1 Biochemical Analysis of the Polycystin-1 Complexity
Generated by Proteolytic Cleavage at the G Protein-Coupled
Receptor Proteolysis Site ......................................................................1
Rebecca Walker, Hangxue Xu, Qiong Huang, and Feng Qian
Chapter 2 Structural Determination of the Polycystin-2 Channel by
Electron Cryo-Microscopy .................................................................27
Qinzhe Wang and Erhu Cao
Chapter 3 Recording Ion Channels in Cilia Membranes ....................................51
Leo C.T. Ng, Amitabha Mukhopadhyay, Thuy N. Vien,
and Paul G. DeCaen
Chapter 4 Electrophysiological Recording of a Gain-of-Function
Polycystin-2 Channel with a Two-Electrode Voltage Clamp .............69
Courtney Ng, Zhifei Wang, Bin Li, and Yong Yu
Chapter 5 Functional Studies of PKD2 and PKD2L1 through Opening
the Hydrophobic Activation Gate .......................................................87
Wang Zheng, Lingyun Wang, Jingfeng Tang, Ji-Bin Peng,
and Xing-Zhen Chen
Chapter 6 Analyzing the GPCR Function of Polycystin-1................................103
Stephen C. Parnell, Robin L. Maser, Brenda S. Magenheimer,
and James P. Calvet
Chapter 7 Methods to Study the Vasculature in ADPKD ................................127
Patricia Outeda and Terry Watnick
v
vi Contents
Chapter 8 Energy Metabolism, Metabolic Sensors, and Nutritional
Interventions in Polycystic Kidney Disease .....................................161
Sonu Kashyap and Eduardo Nunes Chini
Chapter 9 “Kidney in a Dish” Organoids for PKD ...........................................177
Nelly M. Cruz and Benjamin S. Freedman
Chapter 10 Rodent Autosomal Dominant Polycystic Kidney
Disease Models ................................................................................195
Sara J. Holditch, Raphael A. Nemenoff, and Katharina Hopp
Chapter 11 Using C. elegans as a Model in PKD ...............................................247
Juan Wang and Maureen Barr
Chapter 12 Approaches to Studying Polycystic Kidney Disease in Zebrafish .......267
Jingyu Li and Ying Cao
Chapter 13 Investigation of DNA Methylation in Autosomal Dominant
Polycystic Kidney Disease ...............................................................293
Ewud Agborbesong and Xiaogang Li
Chapter 14 Molecular Diagnosis of Autosomal Dominant Polycystic
Kidney Disease .................................................................................309
Matthew Lanktree, Amirreza Haghighi, Xueweng Song,
and York Pei
Index ......................................................................................................................331
Preface
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common,
life-threatening genetic diseases. Twenty-five years after the first cloning of PKD1,
one the two major causal loci for ADPKD, and the subsequent intensive investigation,
the pace of progress in understanding the pathogenesis of ADPKD, the function of
polycystins, and the development of therapeutics has been inadequate due to enormous
technical challenges and availability of appropriate experimental models. The approval
of the very first pharmacological treatment, tolvaptan, by the U.S. Food and Drug
Administration (FDA) in 2018 has once again inspired tremendous interest in ADPKD
research in the field. In the meantime, the fact that tolvaptan is moderately effective
with significant side effects encourages more research to address the unmet clinical
needs of ADPKD patients. We will thus find an ever-greater need from new biologists
and clinicians seeking proper methodology to study ADPKD and polycystins.
This book focuses on methodology and concepts including research approaches,
practical protocols, and molecular diagnosis used in the study of polycystins and
ADPKD. We envision this book to serve as a reference source with sufficient
information and practical descriptions for those interested in ADPKD and polycystins,
ranging from biologists and clinicians in the field to interested students. However, this
book is not a comprehensive survey of all experimental approaches used in studying
ADPKD, but rather focuses on the protocols that specifically analyze polycystins’
structure and function with biochemical, epigenetic, electrophysiological, and structural
methods, as well as the best-available functional models, ranging from state-of-the-
art in vitro “kidney-in-a-dish” organoids to in vivo model organisms including simple
nematode, vertebrate zebrafish, and preclinical rodent models. Due to the emerging
evidence suggesting that cardiovascular anomalies, a major cause of morbidity and
mortality in ADPKD patients, are likely primary manifestations independent of
hypertension in ADPKD, as well as the discoveries supporting that cysts in PKD exhibit
an altered energy metabolism similar to the Warburg effect in many cancer cells, the
book extends two chapters specifically on the study of cardiovascular disorders and
metabolism in ADPKD. The book assumes a rudimentary knowledge of cell biology,
biochemistry, and electrophysiology. The references are by no means exhaustive, and
we apologize to all our colleagues whose work has not been included or cited.
We could not have completed this book without the help of many people. We wish
to express our gratitude to all contributing authors who invested their priceless time to
expedite this project to fruition. We would like to thank Dr. Michael Zhu for inviting
us to start this project and thank the publishing team at CRC Press/Taylor & Francis
for keeping the editing process on track and being extremely patient with repeated
delays due to unexpected but reasonable scenarios that occurred frequently in the
overloaded lives of scientists. Finally, we want to thank our families for putting up
with us and recognizing the value of our task.
Jinghua Hu
Yong Yu
vii

Editors
Jinghua Hu, PhD, is an associate professor of biochemistry and molecular biology
in the Department of Biochemistry and Molecular Biology and an associate professor
of medicine in the Division of Nephrology and Hypertension at the Mayo Clinic. Dr.
Hu received a PhD from the Chinese Academy of Science in 2001. He completed
his postdoctoral training with Dr. Maureen M. Barr at the University of Wisconsin–
Madison and was recruited as an assistant professor of medicine and BMB in 2008
and promoted to associate professor in 2014. Dr. Hu’s research systematically
explores cilia-related human diseases, collectively termed ciliopathies, by using
various disease models from the inexpensive and efficient nematode C. elegans in
cultured mammalian cells and genetically engineered rodent models. His lab has
developed numerous models of ciliopathies, with the goals of understanding the
pathogenesis and testing the potential for diagnostic/therapeutic purposes. Dr. Hu
has administered numerous extramural funding sources and presently holds two R01
grants from NIDDK and is the co-principal investigator on another two R01s with
his Mayo colleagues. Dr. Hu serves as a director of the Model Organism Core in
the NIH-funded Mayo Translational PKD Center and is a member of the Scientific
Advisory Committee of the PKD foundation.
Yong Yu, PhD, is an associate professor and the director of graduate studies in the
Department of Biological Sciences at St. John’s University, Queens, New York. He
received a BS from the Ocean University of China, Qingdao, China, in 1996, and a
PhD from the Shanghai Institute of Plant Physiology and Ecology, Chinese Academy
of Sciences, in 2001. He was trained as a postdoctoral research scientist first in the
Center for Molecular Recognition with Dr. Arthur Karin, then in the Department of
Biological Sciences with Dr. Jian Yang at Columbia University, New York, from 2001
to 2006. He was an associate research scientist at Columbia University from 2006
to 2012. In 2012, he became an assistant professor in the Department of Biological
Sciences at St. John’s University and was promoted to associate professor in 2016.
Dr. Yu’s research interests include the structure and function of receptor and ion
channels, especially transient receptor potential (TRP) channels and polycystins.
Dr. Yu’s main contributions in PKD research include molecular determination of
the subunit stoichiometry of the polycystin-1/polycsytin-2 complex, generation of
the first gain-of-function mutants of the polycystin-2 channel and the polycystin-1/
polycystin-2 complex channel, and characterization of the ion channel function of
polycystin-1 in the polycystin-1/polycystin-2 complex and of PKD1L3 in the PKD1L3/
polycystin-L complex.
ix