Functional interaction of claudins in renal ion transport.

• Applicant: Professorin Dr. Dorothee Günzel
• Subject Area: Anatomy and Physiology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318374368

Tight junctions act as paracellular diffusion barriers between neighboring epithelial cells but also contain paracellular channels for cations, anions and/or water which are composed of certain members of the claudin protein family. In the kidney, claudins have a distinct expression pattern and thus define paracellular properties of specific nephron segments.During the first funding period, the two major claudin-10 (CLDN10) isoforms proved to be of special interest. CLDN10a acts as an anion channel and is expressed in the proximal tubule. CLDN10b forms cation channels and is highly expressed in the thick ascending limb of Henle’s loop (TAL). Extrarenally, it is found in various glands and in the gut.Patients suffering from HELIX syndrome (hypohydrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, xerostomia) carry mutations in the CLDN10 gene which either affect both isoforms or only CLDN10b. To elucidate the underlying pathophysiology, we will investigate the roles of CLDN10a and -10b in kidney, colon and sweat gland function.Major aims are (A) to unravel the compensatory mechanisms in the kidney of Cldn10a-deficient mice, (B) to separate effects of Cldn10b deficiency in TAL and thin limbs on urine osmolarity and volume, (C) to characterize the role of CLDN10b in extrarenal tissues, (D) to study the involvement of CLDN10b dysregulation in the pathogenesis of further diseases, especially in cholinergic urticaria, (E) to investigate the zebrafish Cldn10b/15 complex to identify decisive structural elements of CLDN10b/15 selectivity filters.

• DFG Programme: Research Grants