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Thesis Defence

PhD degree for Mohammad Alsady

Mohammad Alsady defense 21 Jun 2018

Mohammad Alsady obtained his Ph.D. degree in the Medical Sciences of the Radboud University Nijmegen after the successful defense of his thesis entitled "Molecular characterization of water balance disturbances".



Aims of the thesis 

The maintenance of water homeostasis is critical for body and cell function. However, this tightly-regulated mechanism is disturbed in diseases such as Li-NDI and SIADH. Therefore, the aim of this thesis was to gain insight into the pathophysiology of water balance disturbances with the focus on renal side effects of lithium and SIADH. Chapters 2-7 focus on the renal effects of lithium, whereas chapters 8 and 9 focus on the role of AQP2 in other renal pathologies.

The first chapters focus on the renal side effects of lithium. Beside the downregulation of AQP2 water channel in the collecting duct, lithium treatment decreases the percentage of these cells in the long-term resulting in a phenomenon called collecting duct remodeling, which is paradoxical as lithium induces proliferation in these cells specifically. In chapter 2, we investigate the cause of lithium-induced collecting duct remodeling. Moreover, Li-NDI patients are currently treated with amiloride and hydrochlorothiazide. Amiloride blocks the entrance of lithium into the principal cells through ENaC, but hydrochlorothiazide was shown to have anti carbonic anhydrase activity beside the inhibition of the sodium chloride cotransporter (NCC) (60, 61). Accordingly, in Chapter 3 we explored whether acetazolamide, that is specific carbonic anhydrase inhibitor, is a better treatment for Li-NDI than co-treatment of amiloride and hydrochlorothiazide. Furthermore, proliferating cells often generate their energy by a process called "aerobic glycolysis", which takes place regardless of tissue oxygen levels. In Chapter 4, we investigated whether lithium induces aerobic glycolysis in principal cells of the collecting duct and if the inhibition of glycolysis could serve as an alternative treatment for Li-NDI in mpkCCD cells and mice. One of the metabolites that is extensively produced during aerobic glycolysis and glutaminolysis is succinate. Secreted succinate binds to the succinate receptor 1 (SUCNR1), which is also expressed at the plasma membrane of tubular cells. In chapter 5, therefore, we studied the role of SUCNR1 in the development of Li-NDI. Additionally, as mentioned earlier, amiloride blocks the entrance of lithium into the principal cells and prevents Li-NDI. However, it still not known whether amiloride attenuates proliferation and collecting duct remodeling that are induced by lithium. Therefore, in chapter 6, we explored the other renal ameliorating effects of amiloride. Furthermore, as long-term lithium treatment is associated with development of renal interstitial fibrosis, in Chapter 7 we present mice as a model to investigate lithium induced interstitial fibrosis.

In the remaining chapters, we focused on the role of AQP2 water channel in other renal pathologies. In Chapter 8, we employed RNA-seq technique to determine pathways involved in the development of syndrome of inappropriate antidiuretic hormone secretion (SAIDH). In chapter 9, we employed mpkCCD cells and with the help of an NDI patient lacking AQP2, we tested the potential role of AQP2 in cell migration, proliferation and microcyst formation. Finally, the thesis concludes with a summary and general discussion presented in chapter 10.   

Click here to access Mohammads' thesis digitally. 

 


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