Information
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| Joost Hoenderop and René Bindels |
The Ion Transport group forms a dynamic team of researchers
consisting of Post.docs, PhD students and technicians. The group is
supervised by Prof. dr. Joost Hoenderop and Prof. dr. René
Bindels. Their research line benefits from fruitful
collaborations within the Radboud University Nijmegen Medical
Centre with the departments of Human Genetics, Pediatrics and
Biochemistry and other (inter)national departments.
Research focuses on the elucidation of the molecular mechanisms
underlying epithelial transport disorders including kidney and
small intestine. The major emphasis is currently on the novel
epithelial calcium (TRPV5 & TRPV6) and magnesium (TRPM6 &
TRPM7) channels that constitute the rate-limiting calcium /
magnesium influx pathways in epithelia. In addition, they
investigate the role of renal sodium transporters (NKCC2, NCC,
ENaC) in essential hypertension and contribute to the
multidisiplinary effort to establish a biokidney. For more details
see below:
Calcium balance
The
successful cloning by our group of the new calcium channel TRPV5
offers a realistic approach to study the physiological, functional
and regulatory aspects of this calcium influx pathway. Knowledge of
TRPV5 and TRPV6 functioning will, in particular, provide a
molecular basis for achieving a better understanding of calcium
related disorders in which (re)absorption processes are disturbed.
Alterations in calcium (re)absorption are present in many
physiological and pathophysiological states including
hypercalciuric stone disease, osteoporosis, chronic renal failure,
diabetes, chronic administration of diuretics and
immunosuppressors. Mice lacking TRPV5 display diminished active
calcium reabsorption despite enhanced vitamin D levels, causing
severe hypercalciuria.
Renal sodium transporters
Hypertension represents a health problem, affecting 1.25
billion people worldwide and is responsible for
cardiovascular and end-stage renal disease. The molecular
pathogenesis is not well understood. Multiple genes with variant
alleles and different environmental factors contribute to
hypertension. Genetic disorders distressing blood pressure, like
Gitelman's syndrome and Pseudohypoaldosteronism-II, have firmly
established the renal responsibility and particularly the
thiazide-sensitive
Na+:Cl- cotransporter
(NCC) in blood pressure maintenance.
Magnesium balance
Magnesium
is of great importance by its function in neuromuscular
excitability, protein synthesis and nucleic acid stability. After
years of research, progress has recently been made in the
identification of pivotal proteins contributing to the delicate
body magnesium balance. The epithelial magnesium channel TRPM6 was
identified as the responsible gene in patients with severe
hypomagnesemia and is composed of a linked channel subunit and
alpha-kinase domain. TRPM6 acts as the gatekeeper for magnesium
(re)absorption in the intestine and kidney and, therefore, the
overall body magnesium balance. Recently, we identified the
epidermal growth factor (EGF) as an autocrine/paracrine
magnesiotropic hormone that regulates renal magnesium reabsorption
by regulating the activity of TRPM6.
Biokid project
The BioKid
aims at developing living membranes for an intradialytic biological
kidney support device. We will develop a cell device (BioKid)
capable of effective clearance of toxins ex vivo. The BioKid will
comprise of multiple so-called living membranes, i.e. tight
monolayers of human renal epithelial cells that are grown on newly
designed semi-permeable bioactive polymer membranes. A unique
supramolecular approach will be used to develop a 2D bioactive
polymer membrane that regulates long-lived monolayer integrity and
cell viability under uremic conditions.
