ArticlePflugers Archiv : European journal of physiology2014
Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin.
Article in Pflugers Archiv : European journal of physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
- Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2022Trial
- Physiologic mechanisms underlying polycystic kidney disease.Physiological reviews · 2025Review
- Novel Potential Therapeutic Targets in Autosomal Dominant Polycystic Kidney Disease from the Perspective of Cell Polarity and Fibrosis.Biomolecules & therapeutics · 2024Review
- TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases.Signal transduction and targeted therapy · 2023Review
- Polycystin-1 regulates cell proliferation and migration through AKT/mTORC2 pathway in a human craniosynostosis cell model.Journal of cellular and molecular medicine · 2022Article
- Polycystin-1 and hydrostatic pressure are implicated in glioblastoma pathogenesis in vitro.Journal of cellular and molecular medicine · 2022Article
- Autophagy in renal fibrosis: Protection or promotion?Frontiers in pharmacology · 2022Review
- Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death.International journal of molecular sciences · 2021Article
- Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease.Genes · 2021Review
- Enhanced MCP-1 Release in Early Autosomal Dominant Polycystic Kidney Disease.Kidney international reports · 2021Article
- Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment.International journal of molecular sciences · 2020Review
- Lowe syndrome patient cells display mTOR- and RhoGTPase-dependent phenotypes alleviated by rapamycin and statins.Human molecular genetics · 2020Article
- Fundamental insights into autosomal dominant polycystic kidney disease from human-based cell models.Pediatric nephrology (Berlin, Germany) · 2019Article
- Oxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression?Pediatric nephrology (Berlin, Germany) · 2019Article
- The combination of metformin and 2-deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease.British journal of pharmacology · 2019Article
- Metabolism and mitochondria in polycystic kidney disease research and therapy.Nature reviews. Nephrology · 2018Review
- MicroRNA501-5p induces p53 proteasome degradation through the activation of the mTOR/MDM2 pathway in ADPKD cells.Journal of cellular physiology · 2018Article
- Activation of Calcium-Sensing Receptor increases intracellular calcium and decreases cAMP and mTOR in PKD1 deficient cells.Scientific reports · 2018Article
- Metformin Inhibits Cyst Formation in a Zebrafish Model of Polycystin-2 Deficiency.Scientific reports · 2017Article
- Double inhibition of cAMP and mTOR signalling may potentiate the reduction of cell growth in ADPKD cells.Clinical and experimental nephrology · 2017Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss-of-function mutations in either PKD1 or PKD2 genes, which encode polycystin-1 (TRPP1) and polycystin-2 (TRPP2), respectively. Increased activity of the mammalian target of rapamycin (mTOR) pathway has been shown in PKD1 mutants but is less documented for PKD2 mutants. Clinical trials using mTOR inhibitors were disappointing, while the AMP-activated kinase (AMPK) activator, metformin is not yet tested in patients. Here, we studied the mTOR activity and its upstream pathways in several human and mouse renal cell models with either siRNA or stable knockdown and with overexpression of TRPP2. Our data reveal for the first time differences between TRPP1 and TRPP2 deficiency. In contrast to TRPP1 deficiency, TRPP2-deficient cells did neither display excessive activation of the mTOR-kinase complex nor inhibition of AMPK activity, while ERK1/2 and Akt activity were similarly affected among TRPP1- and TRPP2-deficient cells. Furthermore, cell proliferation was more pronounced in TRPP1 than in TRPP2-deficient cells. Interestingly, combining low concentrations of rapamycin and metformin was more effective for inhibiting mTOR complex 1 activity in TRPP1-deficient cells than either drug alone. Our results demonstrate a synergistic effect of a combination of low concentrations of drugs suppressing the increased mTOR activity in TRPP1-deficient cells. This novel insight can be exploited in future clinical trials to optimize the efficiency and avoiding side effects of drugs in the treatment of ADPKD patients with PKD1 mutations. Furthermore, as TRPP2 deficiency by itself did not affect mTOR signaling, this may underlie the differences in phenotype, and genetic testing has to be considered for selecting patients for the ongoing trials.
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