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Thesis Defence

PhD degree for Omar Tutakhel

Promotie Omar 1 15 Feb 2018

Omar Tutakhel successfully defended his thesis entitled "Alternative splicing-derived isoforms of the NaCl cotransporter and their role in hypertension". During his PhD research Omar studied in humans the role of the NaCl cotransporter in renal salt handling under the supervision of Profs. René Bindels, Joost Hoenderop, Ewout Hoorn (promotors) and dr. Jenny van der Wijst (co-promotor).

Aims of the thesis 

The thiazide-sensitive NaCl cotransporter (NCC) is an important pharmacological target in the treatment of hypertension. Human SLC12A3 gene, encoding NCC, gives rise to three isoforms. While the third isoform, NCC3 has been the focus of intense research over the the last decades, the regulation and function of isoforms 1 and 2 (NCCSV) in blood pressure control remained largely unexplored. NCCSV is only present in humans and higher primates and to date, the detailed localization of NCCSV in human kidney, the regulatory network, the relationship with NCC3 and its relevance in renal Na+ handling remains to be elucidated. A better understanding of these isoforms is critical to unravel the molecular events underlying the pathogenesis of essential hypertension, and to develop effective therapeutic strategies to combat the dysregulation of blood pressure. Therefore, the aim of this thesis was to study the role of all three NCC isoforms in various (patho)physiological conditions. First the goal was to determine the abundance and localization of previously underrepresented NCC isoforms compared to NCC3 in the human kidney. Additionally, the functional properties of the NCCSV as well as its regulation in physiological conditions was studied. Subsequently, the effect of various anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients, and to explore the relationship between NCC abundance in uEVs and changes in blood pressure was studied. Furthermore, we investigated the role of the new S811 phosphorylation site in NCCSV function, determine the interaction of NCCSV with NCC3 and studied the effect of NCCSV S811 phosphorylation on the function of NCC3. Next, a large-scale study was performed to investigate the effect of CNIs, including cyclosporine A and tacrolimus on the abundance of both total and phosphorylated NCC in uEVs, and assessed whether NCC abundance in uEVs predicts the blood pressure response to thiazide diuretics. In order to confirm the effect of CNIs on NCC in the kidney, an ex vivo study was conducted in mice cortical tubules exposed to cyclosporine. Finally, in mice, the effect of high sodium (Na+)-low potassium (K+) diet was not only investigated on NCC regulation, but its affect was also studied on Mg2+, Ca2+ and phosphate (Pi) homeostasis.   

Click here to access Omar's thesis digitally.

Click here to see the media attention for his thesis.

Click here to read paper in kidney news.

Promotie Omar

 

 


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