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Proc Natl Acad Sci U S A ; 114(27): 7154-7159, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28630289

RESUMO

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 [Formula: see text]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.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Dendroaspis , Peptídeos Natriuréticos/farmacologia , Peptídeos/farmacologia , Doenças Renais Policísticas/tratamento farmacológico , Receptores de Vasopressinas/genética , Venenos de Serpentes/farmacologia , Animais , Benzazepinas/farmacologia , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , AMP Cíclico/metabolismo , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Doenças Renais Policísticas/metabolismo , Transdução de Sinais , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Fatores de Tempo , Tolvaptan , Tripsina/química
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