ArticleEBioMedicine2019
Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 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
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- The Role of Immune Cells as Modulators of Progression in Polycystic Kidney Disease: A Systematic Review.Kidney360 · 2026Pooled it
- Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.Clinical journal of the American Society of Nephrology : CJASN · 2022Trial
- Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD).Kidney international · 2021Trial
- Species, cell proliferation state and oxygen partial pressure are major factors in the in vitro toxicity of repurposed potential ADPKD drugs in human and murine renal proximal tubule cells.Archives of toxicology · 2026Article
- The Role of Mitochondria in Polycystic Kidney Disease.International journal of molecular sciences · 2026Review
- TLR2 Activation Enhances Inflammatory Signaling and Accelerates Cyst Growth and Renal Fibrosis in Polycystic Kidney Disease Mice.International journal of molecular sciences · 2026Article
- AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.Nature metabolism · 2026Review
- TargetingbioRxiv : the preprint server for biology · 2025Article
- SGLT2 inhibition for patients with ADPKD - closing the evidence gap.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025Review
- Inhibition of the inflammasome ameliorates orthologous polycystic kidney disease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Transforming advancing autosomal dominant polycystic kidney disease care: investigating new horizons in treatment and research.Inflammopharmacology · 2025Review
- Therapies in autosomal dominant polycystic kidney disease: beyond tolvaptan.Current opinion in nephrology and hypertension · 2025Review
- Physiologic mechanisms underlying polycystic kidney disease.Physiological reviews · 2025Review
- Activation of toll-like receptor 2 promotes the expression of inflammatory mediators and cell proliferation of human polycystic kidney disease cells.Cellular signalling · 2025Article
- Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease: Role in Cystogenesis and Novel Therapeutic Approaches.Biomedicines · 2025Review
- Renoprotective effects of combination therapy with tolvaptan and dapagliflozin in autosomal dominant polycystic kidney disease: a four-case series.CEN case reports · 2025Article
- Sodium-Glucose Cotransporter-2 Inhibitor Therapy and Longitudinal Changes in Kidney Function among Veterans with Autosomal Dominant Polycystic Kidney Disease.Clinical journal of the American Society of Nephrology : CJASN · 2025Article
- Outcomes of Patients With Autosomal Dominant Polycystic Kidney Disease Prescribed SGLT2 Inhibitors in British Columbia: A Single-Arm Retrospective Cohort Study.Canadian journal of kidney health and disease · 2025Article
- The Influence of Non-Pharmacological and Pharmacological Interventions on the Course of Autosomal Dominant Polycystic Kidney Disease.Nutrients · 2024Review
- Potential Add-On Benefits of Dietary Intervention in the Treatment of Autosomal Dominant Polycystic Kidney Disease.Nutrients · 2024Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMultiple preclinical studies have highlighted AMP-activated protein kinase (AMPK) as a potential therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Both metformin and canagliflozin indirectly activate AMPK by inhibiting mitochondrial function, while salsalate is a direct AMPK activator. Metformin, canagliflozin and salsalate (a prodrug dimer of salicylate) are approved for clinical use with excellent safety profile. Although metformin treatment had been shown to attenuate experimental cystic kidney disease, there are concerns that therapeutic AMPK activation in human kidney might require a higher oral metformin dose than can be achieved clinically.
methodsIn this study, we tested metformin-based combination therapies for their additive (metformin plus canagliflozin) and synergistic (metformin plus salsalate) effects and each drug individually in an adult-onset conditional Pkd1 knock-out mouse model (n = 20 male/group) using dosages expected to yield clinically relevant drug levels.
findingsCompared to untreated mutant mice, treatment with salsalate or metformin plus salsalate improved kidney survival (i.e. blood urea nitrogen <20 mmol/L at the time of sacrifice) and reduced cystic kidney disease severity. However, the effects of metformin plus salsalate did not differ from salsalate alone; and neither metformin nor canagliflozin was effective. Protein expression and phosphorylation analyses indicated that salsalate treatment was associated with reduction in mTOR (mammalian target of rapamycin) activity and cellular proliferation in Pkd1 mutant mouse kidneys. Global gene expression analyses suggested that these effects were linked to restoration of mitochondrial function and suppression of inflammation and fibrosis.
interpretationSalsalate is a highly promising candidate for drug repurposing and clinical testing in ADPKD.
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Registered trials
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