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Ion Transport

Information

Rene - joost - 2012
René Bindels and Joost Hoenderop

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, Nephrology 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 and animation movies see below:

Calcium balance

Movie-KlothoThe 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. TRPV5 is uniquely regulated by the anti-aging hormone klotho which hydrolysis the N-glycan to stabilize the channel in the membrane. 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.

 

Renal sodium transporters

Movie-NCC 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

Movie-TRPM6 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

Movie-BiokidThe 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.

 

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