PUBLICATION
Autophagy Activators Suppress Cystogenesis in an Autosomal Dominant Polycystic Kidney Disease Model
- Authors
- Zhu, P., Sieben, C.J., Xu, X., Harris, P.C., Lin, X.
- ID
- ZDB-PUB-161224-10
- Date
- 2017
- Source
- Human molecular genetics 26(1): 158-172 (Journal)
- Registered Authors
- Lin, Xueying, Xu, Xiaolei, Zhu, Ping
- Keywords
- none
- MeSH Terms
-
- Animals
- Autophagy/drug effects*
- Autophagy-Related Protein 5/metabolism
- Carbamazepine/pharmacology
- Cells, Cultured
- Disease Models, Animal
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology
- Epithelial Cells/drug effects
- Epithelial Cells/metabolism
- Epithelial Cells/pathology
- Mice
- Mice, Knockout
- Polycystic Kidney, Autosomal Dominant/metabolism
- Polycystic Kidney, Autosomal Dominant/pathology
- Polycystic Kidney, Autosomal Dominant/prevention & control*
- Sirolimus/pharmacology
- TOR Serine-Threonine Kinases/metabolism
- TRPP Cation Channels/physiology*
- Zebrafish
- PubMed
- 28007903 Full text @ Hum. Mol. Genet.
Citation
Zhu, P., Sieben, C.J., Xu, X., Harris, P.C., Lin, X. (2017) Autophagy Activators Suppress Cystogenesis in an Autosomal Dominant Polycystic Kidney Disease Model. Human molecular genetics. 26(1):158-172.
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 It is one of the most common heritable human diseases with eventual development of renal failure; however, effective treatment is lacking. While inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst expansions in animal models, results from clinical studies are controversial, prompting further mechanistic studies of mTOR-based therapy. Here, we aim to establish autophagy, a downstream pathway of mTOR, as a new therapeutic target for PKD. We generated zebrafish mutants for pkd1 and noted cystic kidney and mTOR activation in pkd1a mutants, suggesting a conserved ADPKD model. Further assessment of the mutants revealed impaired autophagic flux, which was conserved in kidney epithelial cells derived from both Pkd1-null mice and ADPKD patients. We found that inhibition of autophagy by knocking down the core autophagy protein Atg5 promotes cystogenesis, while activation of autophagy using a specific inducer Beclin-1 peptide ameliorates cysts in the pkd1a model. Treatment with compound autophagy activators, including mTOR-dependent rapamycin as well as mTOR-independent carbamazepine and minoxidil, markedly attenuated cyst formation and restored kidney function. Finally, we showed that combination treatment with low doses of rapamycin and carbamazepine was able to attenuate cyst formation as effectively as single treatment with a high dose of rapamycin alone. In summary, our results suggested a modifying effect of autophagy on ADPKD, established autophagy activation as a novel therapy for ADPKD, and presented zebrafish as an efficient vertebrate model for developing PKD therapeutic strategies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping