Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Proc Natl Acad Sci U S A ; 119(30): e2121267119, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35867829

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) affects more than 500,000 individuals in the United States alone. In most cases, ADPKD is caused by a loss-of-function mutation in the PKD1 gene, which encodes polycystin-1 (PC1). Previous studies reported that PC1 interacts with atypical protein kinase C (aPKC). Here we show that PC1 binds to the ζ isoform of aPKC (PKCζ) and identify two PKCζ phosphorylation sites on PC1's C-terminal tail. PKCζ expression is down-regulated in patients with ADPKD and orthologous and nonorthologous PKD mouse models. We find that the US Food and Drug Administration-approved drug FTY720 restores PKCζ expression in in vitro and in vivo models of polycystic kidney disease (PKD) and this correlates with ameliorated disease progression in multiple PKD mouse models. Importantly, we show that FTY720 treatment is less effective in PKCζ null versions of these PKD mouse models, elucidating a PKCζ-specific mechanism of action that includes inhibiting STAT3 activity and cyst-lining cell proliferation. Taken together, our results reveal that PKCζ down-regulation is a hallmark of PKD and that its stabilization by FTY720 may represent a therapeutic approach to the treat the disease.


Assuntos
Cloridrato de Fingolimode , Rim Policístico Autossômico Dominante , Proteína Quinase C , Animais , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Humanos , Camundongos , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/enzimologia , Proteína Quinase C/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...