Impact Objectives• Explore the underlying cellular and molecular causes of the Chronic
Kidney Disease (CKD)• Investigate the potential to develop a drug that inhibits thedevelopment or progression of CKD

A broad approach
to kidney disease
Professor Reiko Inagi discusses her work and passion on tackling chronic kidney disease at an organ,
cellular and molecular level
What type ofresearch is being
carried out at theDivision of Chronic
Kidney Disease
Pathophysiology,
the University ofTokyo Graduate School of Medicine? Whatis the impact of this work and who will
ultimately benefit from your research?
We are performing studies about thepathophysiology of organelle stress suchas endoplasmic reticulum (ER) stress andmitochondrial stress, especially underhypoxia, oxidative stress or metabolic
stress condition, all of which accelerate thedevelopment and progression of chronic
kidney disease (CKD). Among CKD, diabetic
kidney disease (DKD) is the leading causeof end-stage kidney disease (ESKD), andwe are also studying the pathophysiologyof DKD utilising omics approaches. Thesestudies will give us new insights into thepathophysiology of CKD and DKD, leading
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to the development of novel therapeuticstrategies of a broad range of kidneydisease, a growing global problem.
You are working to develop more effective
CKD preventative and therapeutic strategies.
How do you envisage your findings will beapplied to healthcare settings?
We are elucidating the pathophysiology of
CKD and finding surrogate markers andnovel therapeutic targets. Our findings willbe translated into real-world applications forhealthy longevity with a healthy kidney.
You work with a number of international
students. Can you talk about the value of
this to both your studies and the students,
as well as the importance of supporting
early stage researchers?
It is important to support early stage
researchers because they are the future ofscience. They are the ones who will solve
the problems that we cannot answer atthis moment. To work and discuss withinternational students or visiting researchers
stimulates our projects through the diverse
points of view that give us a new insight.
How will the knowledge you have gathered
be shared with other academic institutions
and healthcare organisations?
I publish our works in peer-reviewed
journals and give talks at scientificmeetings. Those at other academic
institutions and healthcare organisations
share our updated finding by reading ourpapers and listening to my lectures.
What does the future hold for your research?
What would you like to be working on in thenear future?
I would like to be working on developing
new surrogate markers and drugs for theprevention of kidney disease, especially
CKD and DKD. l

A new responseto an old problem
Researchers in the Division of Chronic Kidney Disease Pathophysiology, the University of Tokyo
Graduate School of Medicine, are tackling the growing problem of chronic kidney disease througha comprehensive omics approachChronic diseases are quickly outstripping
other reasons for sources of morbidity indeveloped societies. Many developed nations
have to deal with the modern problem of anageing population and large sections of thepopulation are now growing old.
Medical care for the aged has improved
dramatically over this time period, however,many fundamental aspects of ageing are
not entirely understood. Put quite simply,
it is not yet clear what causes ageing andwhy it has such a dramatic effect on thehomeostasis and longevity of the body.
Along with the problem of ageing, thesesame nations are also those that have thehighest rates of chronic diseases, such as
lifestyle-related diseases, including diabetes,
cardiovascular disease and hypertension.
These two factors together mean thatdiseases and disorders that result from thebreakdown of homeostatic pathways arebecoming ever more important in developedcountries.
UNDERLYING PATHOGENICMECHANISMS
Chronic kidney disease (CKD) is the mostneglected disorder that is becoming
extremely prevalent. An estimated 850
million people are affected by kidney disease
globally, representing one in 10 of the global
population. The scale of the disease isclearly huge. The disease itself often does
not present with many symptoms, however,
if allowed to progress, it can lead to outrightkidney failure or other complications suchas heart attack, arteriosclerosis and stroke.
CKD is also a huge economic burden forsocieties. There is strong evidence that CKD
is a consequence of other long-term chronic
diseases such as diabetes.

However, the underlying cellular andmolecular causes of the CKD are notwell-established. Professor Reiko Inagi,
chief of the Division of Chronic Kidney
Disease Pathophysiology, the Universityof Tokyo Graduate School of Medicine,is investigating the underlying cellularand molecular mechanisms behind CKD.
Understanding these mechanisms is a
crucial step towards developing a novel
drug that may be able to inhibit the diseaseat a molecular level.
Inagi, along with her collaborator Professor
Masaomi Nangaku of the Division ofNephrology and Endocrinology, theUniversity of Tokyo Graduate School ofMedicine and a team of young researchers,
is approaching the investigation of CKD
from various new angles. ‘We have a myriadof different projects including: identifying
the mechanism of destruction of adaptive
signals to various stresses such as oxidative
stress, hypoxia and metabolic disorders inCKD; understanding the pathophysiology
of organelle stress including endoplasmic
reticulum (ER) stress or mitochondrial
stress and organelle crosstalk; clarifying themechanism of functional change in renal
erythropoietin (EPO)-producing cells alongwith the mechanisms of CKD progression;
identifying factors in the exacerbation ofCKD in patients with diabetes; and using
the findings obtained to establish new
CKD treatment strategies,’ explains Inagi.
‘This many-angled approach makes for aclearer overall picture of the biology andbiochemistry of the disease.’ This, in turn,maximises the Division’s ability to findtreatments and propose viable therapeuticsolutions.

CHATTERING ORGANELLES
Previous work from Inagi’s team has
demonstrated a novel link between two key
cellular organelles that plays an importantrole in the progression of CKD. The ER isa cellular structure that is responsible forprotein maturation through the regulationof their correct synthesis, folding anddegradation. Through this, it has a key
function in maintaining the quality ofproteins that is essential for normal cellfunction. ‘We have previously demonstrated
that the ER is also responsible forcommunicating with the mitochondria tocontrol the mitochondrial structure andfunction,’ observes Inagi. ‘Mitochondria are
the energy factories of the cell, producing
the majority of the cell’s adenosine
triphosphate (ATP) molecule, used as
an energy source by all life. Kidneys are
extremely energy-intensive and therefore
their cells, especially proximal tubular cells,
are rich in mitochondria.’ Inagi believes thatthe breakdown in communications between
the ER and the mitochondria is a crucial
factor in the progression of CKD.
Inagi’s research has shown that theunfolded protein response (UPR) pathway
plays an important role in the crosstalk
between the ER and the mitochondria.
The UPR is a stress response that detects
and tries to solve problems involving
deterioration of ER function, ER stress.
‘First it tries to solve the problem and, if
it is unable to do so, it will lead the cell tokill itself through apoptosis,’ she highlights.
Inagi and her team have reported that theactivation of maladaptive UPR pathwaycauses the development/progression of
CKD and DKD as well as an ageing of thekidney. Furthermore, they have found thatwww.impact.pub 83

Project Insights
FUNDING• Japan Society for the Promotion ofScience Grants-in-Aid for Scientific
Research• The research grant from Kyowa Kirin
Co. Ltd.

the maladaptive UPR pathway is at least inpart caused by an accumulation of metabolic
wastes (e.g. uremic toxins) and that this may
be causing disruption in the mitochondria
and thus energy production. They are now
working towards identifying the specificmolecules involved in the UPR that may bepart of this cross-communication betweenorganelles.
A GLOBAL APPROACH
In order to follow up these investigations,
Inagi and her team are utilising the powerof transcriptomics and metabolomics. The
transcriptome is made up of all the genes
currently being expressed. This is usually
measured by proxy through the mRNAlevels of each gene. ‘By analysing thetranscriptome at different times and under
different pathogenic conditions, we will beable to pick out the key genes involved in
CKD and ER-mitochondrial crosstalk,’ notes
Inagi. Metabolomics is the collection of
metabolites in the cell (or organ) at a giventime. Metabolites are the waste products
from energy production and cell survival. The
concentrations at which they are present give
crucial indications of the metabolic state of
the cells being analysed. This metabolic stateis influenced by the health of the cell andshould therefore help build a picture of both
healthy renal cells and those in the throes ofCKD. ‘Combining the data from these two
will provide a fascinating insight into theimportant proteins and pathways involved
and pick out specific proteins and molecules
involved,’ she says.
For the clinical application of the molecularand cellular biological findings based onomics studies, the researchers are utilisingmouse and rat kidney disease models toperform the transcriptome and metabolome
analyses. Specifically, they are looking at theacute and chronic kidney disease models
with or without metabolic disorder (e.g.,diabetes and dyslipidaemia). Her positionat the university hospital also allows her
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group easy access to human biomaterials,
allowing translation of their research to
bed-side utilisation. They are investigating
both glomeruli and renal tubules to evaluate
their crosstalk from the point of view of adecline in kidney function and renal fibrosis.
The metabolomics of these regions will
look at the carbohydrate, lipid and aminoacid metabolic profiles and link these to thetranscriptomics which should show varying
levels of gene expression in range of related
genes. Inagi explains the power of theseexperiments beyond just understanding
pathophysiology of organelle crosstalk. ‘Byusing kidney disease model animals weare studying not only the importance of thelink between organelle crosstalk and kidneydisease, but also the impact of organelle
crosstalk on the maintenance of cellular
homeostasis.’
BROAD IMPACT
The work of the Division of Chronic
Kidney Disease Pathophysiology and theircollaborators has the potential to impact themillions across the globe who suffer fromCKD. This comes at a particularly crucial
juncture where the populations of developed
countries are ageing and becoming extremely
susceptible to chronic diseases. ‘We willdevelop and target a specific molecule
involved in CKD, and we will halt theprogression of the disease and increase thequality of life of many sufferers,’ promises
Inagi. In addition, their findings will also be
important in examining other kidney diseases
and may help in finding solutions to thoseas well. Inagi’s valuable research projects
are well-known worldwide, offering her
numerous occasions to give invited lecturesat international academic conferences. Inagi
has a number of collaborators in the USA,
Europe, and Asia-Pacific regions, allowing
her to tackle the problems from a diverse
and international point of view. In short, theimpact of Inagi and her collaborators’ work
could be far-reaching and essential to help
tackle these challenges. l

COLLABORATORS
Masaomi Nangaku (MD, PhD), Professorand Head, Division of Nephrology andEndocrinology, the University of Tokyo
Graduate School of Medicine. Nangaku is
Executive Councillor of the International
Society of Nephrology, President of theAsian Pacific Society of Nephrology andVice President of the Japanese Society ofNephrology.
TEAM MEMBER
Assistant Professor Tsuyoshi Inoue (MD,PhD), Division of CKD Pathophysiology,
the University of Tokyo Graduate Schoolof Medicine
CONTACTProfessor Reiko Inagi
T: +81 3 3815 5411 (Ext. 36703)
E: inagi-npr@umin.ac.jp
W: http://www.todai-ckd.com
BIO
Professor Reiko Inagi is the Division
Chief of Chronic Kidney Disease
Pathophysiology, the University of Tokyo
Graduate School of Medicine. She
earned her PhD from Nagoya University
Graduate School of Medicine (1990). She
became an assistant professor at Osaka
University School of Medicine (19911998), moved to Tokai University Schoolof Medicine as a lecturer and began her
studies in molecular nephrology. Inagi
received her “Kimoto Award” from theJapanese Society for Dialysis Therapy(2003). Inagi is a councillor/secretaryof Japanese Society of Nephrology
and International Maillard Reaction
Society, an associate editor of Clinicaland Experimental Pharmacology andPhysiology, and Editorial board ofAmerican Journal of Physiology-Renal
Physiology and Kidney International.