Open AccessPF ‐06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity
Author(s) -
Su Limin,
Yuan Haoxing,
Zhang Haoran,
Wang Ruoqi,
Fu Kequan,
Yin Long,
Ren Ying,
Liu Hongli,
Fang Qian,
Wang Junqi,
Guo Dong
Publication year - 2022
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.13459
Subject(s) - ampk , autosomal dominant polycystic kidney disease , activator (genetics) , pi3k/akt/mtor pathway , cystic fibrosis transmembrane conductance regulator , polycystic kidney disease , in vivo , metformin , cyst , ex vivo , chemistry , microbiology and biotechnology , endocrinology , protein kinase a , cancer research , medicine , pharmacology , kidney , kinase , biology , signal transduction , cystic fibrosis , pathology , diabetes mellitus , receptor
Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over‐proliferation of cyst‐lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an adenosine monophosphate‐activated protein kinase (AMPK) activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF‐06409577, an AMPK activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD. Our results demonstrated that PF‐06409577 effectively down‐regulated mammalian target of rapamycin pathway‐mediated proliferation of cyst‐lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator‐regulated cystic fluid secretion. Overall, our data suggest that PF‐06409577 holds therapeutic potential for ADPKD treatment.