ArticleHuman molecular genetics2014
An mTOR anti-sense oligonucleotide decreases polycystic kidney disease in mice with a targeted mutation in Pkd2.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 39 citations in OpenAlex.
- Design of Nanocarriers for Kidney Targeted Delivery of Nucleic Acid Therapeutics.Macromolecular bioscience · 2026Review
- RNA-based therapeutic opportunities for the treatment of kidney diseases.Nature reviews. Nephrology · 2026Review
- Targeting a pathogenic cryptic exon that drives HLRCC to induce exon skipping.Molecular therapy. Nucleic acids · 2025Article
- RNA-Based Therapies in Kidney Diseases.Journal of inflammation research · 2025Review
- mTOR promotes the formation and growth of tertiary lymphoid tissues in the kidney.Frontiers in immunology · 2025Article
- Gene therapy and kidney diseases.Molecular therapy. Methods & clinical development · 2024Review
- Impaired Glucose Metabolism, Primary Cilium Defects, and Kidney Cystogenesis in Glycogen Storage Disease Type Ia.Journal of the American Society of Nephrology : JASN · 2024Article
- Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models.American journal of physiology. Renal physiology · 2024Article
- CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation.Journal of molecular cell biology · 2022Article
- Kidney Cancer and Chronic Kidney Disease: Too Close for Comfort.Biomedicines · 2021Review
- Oligonucleotide-Based Therapies for Renal Diseases.Biomedicines · 2021Review
- Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD.Frontiers in medicine · 2021Review
- mTOR Signaling in Kidney Diseases.Kidney360 · 2020Review
- Apoptosis and autophagy in polycystic kidney disease (PKD).Cellular signalling · 2020Review
- Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease.Cell metabolism · 2019Article
- PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases.International journal of molecular sciences · 2019Review
- TRPP2 dysfunction decreases ATP-evoked calcium, induces cell aggregation and stimulates proliferation in T lymphocytes.BMC nephrology · 2019Article
- A study of sirolimus and mTOR kinase inhibitor in a hypomorphicAmerican journal of physiology. Renal physiology · 2019Article
- Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.Clinical kidney journal · 2018Review
- MicroRNA501-5p induces p53 proteasome degradation through the activation of the mTOR/MDM2 pathway in ADPKD cells.Journal of cellular physiology · 2018Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease in the USA. In human ADPKD studies, sirolimus, a mammalian target of rapamycin complex 1 (mTORC1) inhibitor, had little therapeutic effect. While sirolimus robustly inhibits mTORC1, it has a minimal effect on mTOR complex 2 (mTORC2). Polycystic kidneys of Pkd2WS25/- mice, an orthologous model of human ADPKD caused by a mutation in the Pkd2 gene, had an early increase in pS6 (marker of mTORC1) and pAktSer(473) (marker of mTORC2). To investigate the effect of combined mTORC1 and 2 inhibition, Pkd2WS25/- mice were treated with an mTOR anti-sense oligonucleotide (ASO) that blocks mTOR expression thus inhibiting both mTORC1 and 2. The mTOR ASO resulted in a significant decrease in mTOR protein, pS6 and pAktSer(473). Pkd2WS25/- mice treated with the ASO had a normalization of kidney weights and kidney function and a marked decrease in cyst volume. The mTOR ASO resulted in a significant decrease in proliferation and apoptosis of tubular epithelial cells. To demonstrate the role of mTORC2 on cyst growth, Rictor, the functional component of mTORC2, was silenced in Madin-Darby canine kidney cell cysts grown in 3D cultures. Silencing Rictor significantly decreased cyst volume and expression of pAktSer(473). The decreased cyst size in the Rictor silenced cells was reversed by introduction of a constitutively active Akt1. In vitro, combined mTORC1 and 2 inhibition reduced cyst growth more than inhibition of mTORC1 or 2 alone. In conclusion, combined mTORC1 and 2 inhibition has therapeutic potential in ADPKD.
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