ArticleJournal of the American Society of Nephrology : JASN2012
Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease.
Article in Journal of the American Society of Nephrology : JASN, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 93 citations in OpenAlex.
- Use of mammalian target of rapamycin inhibitors in patient with autosomal dominant polycystic kidney disease: an updated meta-analysis.International urology and nephrology · 2019Pooled it
- Low-dose rapamycin (sirolimus) effects in autosomal dominant polycystic kidney disease: an open-label randomized controlled pilot study.Clinical journal of the American Society of Nephrology : CJASN · 2014Trial
- Physiologic mechanisms underlying polycystic kidney disease.Physiological reviews · 2025Review
- Rapamycin-encapsulated nanoparticle delivery in polycystic kidney disease mice.Scientific reports · 2024Article
- Reprogramming of Energy Metabolism in HumanInternational journal of molecular sciences · 2024Article
- Folate conjugated nanomedicines for selective inhibition of mTOR signaling in polycystic kidneys at clinically relevant doses.Biomaterials · 2023Article
- Preclinical evaluation of tolvaptan and salsalate combination therapy in aFrontiers in molecular biosciences · 2023Article
- Effects of Suramin on Polycystic Kidney Disease in a Mouse Model of Polycystin-1 Deficiency.International journal of molecular sciences · 2022Article
- AMPK and Polycystic Kidney Disease Drug Development: An Interesting Off-Target Target.Frontiers in medicine · 2022Review
- Translation suppression underlies the restrained COVID-19 mRNA vaccine response in the high-risk immunocompromised group.Frontiers in immunology · 2022Article
- Sirolimus treatment induces dose-dependent involution of the thymus with elevated cellular respiration in BALB/c mice.American journal of translational research · 2022Article
- Interleukin-7 Is Associated with Clinical and Pathological Activities in Immunoglobulin A Nephropathy and Protects the Renal Proximal Tubule Epithelium from Cellular Fibrosis.Current medical science · 2021Article
- Role of DNA-Dependent Protein Kinase in Mediating Cyst Growth in Autosomal Dominant Polycystic Kidney Disease.International journal of molecular sciences · 2021Article
- mTOR Signaling in Kidney Diseases.Kidney360 · 2020Review
- Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment.International journal of molecular sciences · 2020Review
- Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles.EBioMedicine · 2020Article
- Comparison of anti-peritoneal fibrotic effects between an mTORC1-specific blocker and a PI3K/mTOR dual-blocker.Renal failure · 2019Article
- Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease.EBioMedicine · 2019Article
- The Role of Primary Cilia in the Crosstalk between the Ubiquitin⁻Proteasome System and Autophagy.Cells · 2019Review
- The association between autosomal dominant polycystic kidney disease and cancer.International urology and nephrology · 2019Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inhibition of the mammalian target of rapamycin (mTOR) shows beneficial effects in animal models of polycystic kidney disease (PKD); however, two clinical trials in patients with autosomal dominant PKD failed to demonstrate a short-term benefit in either the early or progressive stages of disease. The stage of disease during treatment and the dose of mTOR inhibitors may account for these differing results. Here, we studied the effects of a conventional low dose and a higher dose of sirolimus (blood levels of 3 ng/ml and 30-60 ng/ml, respectively) on mTOR activity and renal cystic disease in two Pkd1-mutant mouse models at different stages of the disease. When initiated at early but not late stages of disease, high-dose treatment strongly reduced mTOR signaling in renal tissues, inhibited cystogenesis, accelerated cyst regression, and abrogated fibrosis and the infiltration of immune cells. In contrast, low-dose treatment did not significantly reduce renal cystic disease. Levels of p-S6Rp(Ser240/244), which marks mTOR activity, varied between kidneys; severity of the renal cystic phenotype correlated with the level of mTOR activity. Taken together, these data suggest that long-term treatment with conventional doses of sirolimus is insufficient to inhibit mTOR activity in renal cystic tissue. Mechanisms to increase bioavailability or to target mTOR inhibitors more specifically to kidneys, alone or in combination with other compounds, may improve the potential for these therapies in PKD.
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