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Osmoregulation

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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:

Osmo3SUCNR1 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.

Osmo2(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.

Osmo1SUCNR1 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.

Osmo4Lithium 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.

 

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