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Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
Published on: September 1, 2015
Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model
Ping Zhu1, Cynthia J Sieben1, Xiaolei Xu1,2
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
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 a 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.
Insights
Autophagy activation is a promising new therapy for Autosomal dominant polycystic kidney disease (ADPKD). Activating autophagy, a cellular process, ameliorates cyst formation and restores kidney function in ADPKD models.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder leading to renal failure with limited treatment options.
- Mechanistic target of rapamycin (mTOR) inhibition shows promise in animal models but yields controversial clinical results, necessitating further investigation.
- Autophagy, a downstream pathway of mTOR, is explored as a novel therapeutic target for ADPKD.
Purpose of the Study:
- To investigate the role of autophagy in ADPKD pathogenesis.
- To establish autophagy activation as a potential therapeutic strategy for ADPKD.
- To utilize zebrafish as a model for developing ADPKD therapies.
Main Methods:
- Generated zebrafish pkd1 mutants to model ADPKD, observing cystic kidneys and mTOR activation.
- Assessed autophagic flux in zebrafish mutants, Pkd1-null mouse cells, and ADPKD patient cells.
- Investigated the effects of autophagy inhibition (Atg5 knockdown) and activation (Beclin-1 peptide, autophagy activators) on cystogenesis.
- Evaluated mTOR-dependent (rapamycin) and mTOR-independent (carbamazepine, minoxidil) autophagy activators in pkd1a mutants.
- Tested combination therapy with rapamycin and carbamazepine.
Main Results:
- Zebrafish pkd1a mutants exhibited cystic kidneys, mTOR activation, and impaired autophagic flux, mirroring ADPKD.
- Autophagy inhibition promoted cystogenesis, while activation ameliorated cysts in the zebrafish model.
- Treatment with rapamycin, carbamazepine, and minoxidil significantly reduced cyst formation and improved kidney function.
- Combination therapy with low-dose rapamycin and carbamazepine was as effective as high-dose rapamycin alone.
Conclusions:
- Autophagy plays a significant role in modulating ADPKD.
- Autophagy activation represents a novel therapeutic approach for ADPKD.
- Zebrafish serve as an effective vertebrate model for discovering and developing ADPKD therapeutic strategies.
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