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A postdoc explains a new assay |
The Osmoregulation group consists of a dynamic team of
researchers consisting of Post.docs, PhD students and technicians.
The group is supervised by Prof. Peter MT Deen. The
fundament of his research lines is a thorough molecular and
cellular understanding of the (patho)physiology of biological
processes and, therefore, his research goes from molecule to man
and benefits from fruitful collaborations with within the Radboud
University Medical Center with the departments of Bio-informatics,
Cell Biology, Nephrology, Internal Medicine, Opthalmology, and
other (inter)national departments.
His two research lines focus on (1) the (patho)physiological
role of mitochondrial metabolites and their receptors in metabolic
disorders and (2) the elucidation of the molecular mechanisms and
development of treatments for water homeostasis disorders. Using
physiogically-relevant cell and animal models, the major emphasis
is currently on identifying the role of the succinate receptor
(SUCNR1) in disorders such as diabetes type 2
(T2DM), chronic kidney disease
(CKD), adrenal cancers (PPGLs),
and age-related macular degeneration (AMD). The
mitochondrial metabolite succinate is released from cells in
conditions of stress after which it can bind the SUCNR1. The
function of the SUCNR1 in metabolic disorders, however, is still
unknown. In addition, we focus on why identified susceptibility
genes cause lithium-induced nephrogenic diabetes insipidus (NDI),
the most common form of polyuria. For more details, see below:
SUCNR1 in
T2DM/CKD. Obesity-induced T2DM and CKD coincide with high
levels of oxidative cell stress. Due to high fat intake, adipocyte
tissue expands strongly, necessitating adaptive angiogenesis. T2DM
developed due to obesity, coincides with loss of arterioles and
demands the usage of another energy source, as cellular glucose
uptake is inhibited. Moreover, the affected arterioles reduce the
filtration capacity of the kidney and lead to CKD, which is a prime
event in development of hypertension and cardiovascular disease.
All these processes involve inflammation. The SUCNR1 is expressed
in adipocytes, kidney, liver, and immune cells. Its expression is
increased with hypoxia and the SUCNR1 is needed for T1DM-induced
hypertension in mice. Recently, we found that mice lacking the
SUCNR1 are partially protected from obesity-induced T2DM and CKD
development. Uncovering the underlying mechanism and the link
between CKD and hypertension is a present focus of our
research.
(SUCNR1 in)
PPGLs. Patients with paraganglioma (PPGLs) have tumors
that originated from adrenal chromaffin cells. The strongest
indicator of malignancy of these tumors is a mutation in subunit B
of the succinate dehydrogenase protein complex (SDHB), which
converts succinate to fumarate as part of the TCA cycle. Mutated
non-functional SDHB leads to increased intracellular and
extracellular succinate and reactive oxygen species (ROS) levels.
Succinate and ROS stabilize HIF by direct intracellular inhibition
of prolylhydroxylases (PHD). In addition, succinate activates the
SUCNR1 extracellularly and we found SUCNR1 expression to be
increased in PPGLs. Its potential role in PPGL development is a
prime topic of our research. Insight in the mechanisms causing
paraganglioma is urgently needed to develop therapeutics for this
disease, but proper models are lacking. Therefore, we are working
on the generation of cell models and zebrafish models using the
CRISPR/Cas9 technology to study the underlying mechanisms of
paraganglioma and test potential therapeutics.
SUCNR1 in
AMD. AMD is one of the most common forms of blindness with
elder people and is characterized by two pathological features: fat
deposition (drusen), which characterizes dry AMD, and inflammation,
which is indicative for wet AMD. Dry AMD is very common (90%), but
there is no treatment. Therefore, there is a large medical need to
develop this, which needs understanding of its etiology. By
absorbing light, eye photoreceptor cells are continuously stressed
and, to cope with this, they continuously shed off their plasma
membranes in their environment. This 'garbage' needs to be removed,
which is done by the underlying retinal pigmental epithelial (RPE)
cells, which express the SUCNR1. Others and we have found that SNPs
in the SUCNR1 increase the risk of developing AMD and, using cells,
animals and patient materials, we want to unravel the
(patho)physiological role of the SUCNR1 in RPE cell functioning and
AMD.
Lithium and
NDI: we have shown that the vasopressin-induced
translocation of the Aquaporin-2 (AQP2) water channel to the apical
membrane of renal principal cells is essential for maintenance of
our body water balance. Disregulation of this process leads to NDI,
a disorder in which patient can urinate up to 20L daily. The most
common form of NDI is found with bipolar disorder patients, which
are treated with lithium and of which 20% develop NDI. We have
shown in cells and mice that lithium induces proliferation of renal
principal cells, leading to the loss of AQP2 and that blocking the
entry of lithium into these cells with amiloride attenuates Li-NDI
development. However, which patients can we rationally advice to
prophylactically take amiloride? To resolve this, we recently
treated 28 mice strains with lithium and, using GWAS analysis, we
identified several potential susceptibility genes for Li-NDI
development. At present, we study why proliferation reduces AQP2
expression and, using CRIPSR/Cas9 technology, the molecular
mechanisms by which differences in expression of the susceptibility
genes influence Li-NDI development.