In the kidney and other epithelial tissues, ion channels are involved in the highly selective and regulated control of ion fluxes across apical and basolateral membranes of epithelial cells. These ion channels are important for intracellular ion homeostasis and transepithelial electrolyte transport. The delicate regulation of these ion channels is pivotal for the maintenance of a healthy ‚milieu interieur‘ as evidenced by severe disease states that result from abnormal ion channel function. Indeed, the study of molecular mechanisms involved in epithelial ion channel regulation is likely to be relevant to understand a range of diseases.
In this context, the group investigates in particular the complex mechanisms involved in the regulation of the epithelial sodium channel (ENaC). Ion flux through ENaC is the rate limiting step for sodium absorption in the aldosterone sensitive distal nephron. The appropriate regulation of ENaC activity is critical for the maintenance of body sodium balance and hence for the long term control of arterial blood pressure. This is evidenced by ‚gain of function‘ mutations of ENaC which cause a hereditary form of severe salt-sensitive arterial hypertension (Liddle’s syndrome).
The molecular mechanisms involved in ENaC regulation are still incompletely understood and involve a complex network of regulatory proteins, kinases, and proteases. Proteolytic activation of ENaC may be pathophysiologically relevant in the context of inflammatory kidney disease and may contribute to sodium retention in nephrotic syndrome. Proteases may also indirectly modulate ion channels. Recently, it has been demonstrated that an activation of the non-selective cation channel TPRV4 (transient receptor potential vanilloid 4) can be mediated by the protease-activated receptor 2 (PAR2). TRPV4 is highly expressed in the distal nephron and collecting duct, but its function is largely unknown. TRPV4 belongs to the same gene family as the polycystins (PKD1 and PKD2) mutated in autosomal dominant polycystic kidney disease (ADPKD). One aim of the group is to characterize the function and regulation of TRPV4 and to explore its possible role in tubular ion transport and renal cyst growth. The group uses a combination of electrophysiological and molecular biological techniques to characterize the functional interaction of ion channels with various receptors, agonists, and regulatory proteins and to identify molecular regions relevant for channel function and regulation.
A better understanding of the molecular mechanisms involved in the regulation of epithelial ion channels will hopefully provide novel insights into their pathophysiological role. This ultimately may lead to new diagnostic and therapeutic concepts.