TU Ilmenau Humbold Bau


Contribution of renal chloride channels to the regulation of blood pressure

Universitätsklinikum Jena
Medizinische Fakultät
2014 - 2018
Else Kröner-Fresenius-Stiftung
Bewilligungssumme, Auftragssumme
236.775,00 €


It is well known that hypertension can result from increased NaCl absorption in the distal nephron of the kidney. Apical uptake of sodium and chloride by epithelial cells of the distal nephron occurs via different transporters and channels. The basolateral exit of chloride is thought to be mediated by ClC-Ka and ClC-Kb chloride channels and their regulatory ß-subunit Barttin. The different contributions of either ClC-Ka or ClC-Kb channels for NaCl reabsorption in the distal nephron are largely unresolved. Disruption of either ClC-Kb or Barttin in men leads to Bartter syndrome, which is characterized by volume depletion and hypotension, while a common activating polymorphism in ClC-Kb (T481S) results in increased blood pressure. In a collaborative phosphoproteomic approach we could show that low salt conditions result in phosphorylation of Barttin at position Ser90. We thus hypothesize that regulation of chloride uptake via ClC-K/Barttin channels is relevant to adapt to different NaCl loads and may in the long term contribute to the development of hypertension. To study the roles of ClC-Kb ion channels in NaCl homeostasis, volume control and blood pressure we have generated a floxed ClC-Kb mouse line which allows us to disrupt ClC-Kb in different segments of the kidney including macula densa cells, which act as salt sensors in the distal nephron and are thus key modulators of body fluid homeostasis. Using different approaches like metabolic cages, in vitro microperfusion of nephron segments, molecular and cell biology, and patch-clamp analysis, we hope to dissect the role of chloride channels from the ClC-K family in renal salt handling and blood pressure control. Our anticipated results will be essential to judge the potential role of ClC-K chloride channels as a target for the treatment of human hypertension.
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