Ciolek, Justyna and Reinfrank, Helen and Quinton, Loic and Viengchareun, Say and Stura, Enrico A. and Vera, Laura and Sigismeau, Sabrina and Mouillac, Bernard and Orcel, Helene and Peigneur, Steve and Tytgat, Jan and Droctove, Laura and Beau, Fabrice and Nevoux, Jerome and Lombes, Marc and Mourier, Gilles and De Pauw, Edwin and Servent, Denis and Mendre, Christiane and Witzgall, Ralph and Gilles, Nicolas (2017) Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114 (27). pp. 7154-7159. ISSN 0027-8424,
Full text not available from this repository. (Request a copy)Abstract
Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein-coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 mu g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KUNITZ-TYPE PROTEASE; MUSCARINIC TOXINS; ALPHA-DENDROTOXIN; TRYPSIN-INHIBITOR; CRYSTAL-STRUCTURE; HIGH-AFFINITY; CYST GROWTH; ANTAGONIST; VENOM; ALPHA(1A)-ADRENOCEPTOR; polycystic kidney disease; Kunitz peptide; snake toxin |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:16 |
| Last Modified: | 28 Feb 2019 12:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1559 |
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