ArticleJournal of the American Society of Nephrology : JASN2016
Inorganic Phosphate Activates the AKT/mTORC1 Pathway and Shortens the Life Span of an α‑Klotho-Deficient Model.
Article in Journal of the American Society of Nephrology : JASN, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- Rapamycin, Not Metformin, Mirrors Dietary Restriction-Driven Lifespan Extension in Vertebrates: A Meta-Analysis.Aging cell · 2025Pooled it
- Klotho Deficiency Impairs Distal Potassium Homeostasis Through mTORC1-Dependent Suppression of ROMK.Acta physiologica (Oxford, England) · 2026Article
- Klotho-Derived Peptide 1 Protects against Acute Kidney Injury by Directly Targeting Mitochondrial ATAD3A.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- α-Klotho as a central integrative signalling hub in cognitive function and neuroprotection in neurodegenerative diseases.Metabolic brain disease · 2026Review
- The effects of elevated phosphate on the kidney - damaging the gatekeeper.Pflugers Archiv : European journal of physiology · 2026Review
- Celastrol Attenuates FGF23 Expression in Osteoblasts by Inhibiting STAT3 Activation.Endocrine, metabolic & immune disorders drug targets · 2026Article
- The Non-Traditional Cardiovascular Culprits in Chronic Kidney Disease: Mineral Imbalance and Uremic Toxin Accumulation.International journal of molecular sciences · 2025Review
- Soft tissue calcifications in chronic kidney disease-beyond the vasculature.Pflugers Archiv : European journal of physiology · 2025Review
- Chronic Kidney Disease-associated Lung Injury Is Mediated by Phosphate-induced MAPK/AKT Signaling.American journal of respiratory cell and molecular biology · 2024Article
- Pathological mechanisms of kidney disease in ageing.Nature reviews. Nephrology · 2024Review
- Phosphate induces inflammation and exacerbates injury from cigarette smoke in the bronchial epithelium.Scientific reports · 2023Article
- The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1.PLoS genetics · 2023Article
- Klotho, Oxidative Stress, and Mitochondrial Damage in Kidney Disease.Antioxidants (Basel, Switzerland) · 2023Review
- KYA1797K, a Novel Small Molecule Destabilizing β-Catenin, Is Superior to ICG-001 in Protecting against Kidney Aging.Kidney diseases (Basel, Switzerland) · 2022Article
- Oxidative Stress Related to Plasmalemmal and Mitochondrial Phosphate Transporters in Vascular Calcification.Antioxidants (Basel, Switzerland) · 2022Review
- Extracellular Phosphate, Inflammation and Cytotoxicity.Advances in experimental medicine and biology · 2022Review
- Topology, tissue distribution, and transcriptional level of SLC34s in response to Pi and pH in grass carp Ctenopharyngodon idella.Fish physiology and biochemistry · 2021Article
- Article
- Multi-element Analysis of Brain Regions from South African Cadavers.Biological trace element research · 2021Article
- Phosphate as a Signaling Molecule.Calcified tissue international · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inorganic phosphate (Pi) has been implicated in the pathogenesis of accelerated aging; however, the underlying mechanisms remain elusive. Herein, we demonstrated in cultured cells and in vivo that increased levels of extracellular Pi activated the AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway by suppressing membrane-bound phosphatase and tensin homolog (PTEN) levels in a manner requiring the sodium-dependent Pi transporter PiT‑1. High levels of extracellular Pi also led to phosphorylation of Ser/Thr clusters in the C‑terminal tail of PTEN, which has been shown to dissociate PTEN from the membrane. Notably, blockade of mTORC1 activity by rapamycin treatment prolonged the life span of hyperphosphatemic α‑Klotho-deficient (Kl(-/-)) mice. Dietary correction of hyperphosphatemia or treatment with rapamycin also rescued the brown adipose tissue dysfunction and oxidative damage observed in Kl(-/-) mice. Furthermore, rapamycin treatment partially rescued these effects and extended the life span when Kl(-/-) mice were maintained on a high-phosphate diet. Finally, rapamycin reduced circulating Pi levels in Kl(-/-) mice, apparently by decreasing the localization of sodium-dependent Pi transport protein 2a at the renal brush border membrane. Therefore, the activation of mTORC1 may create a vicious loop that exacerbates the retention of Pi, which in turn may enhance oxidative damage and ultimately shorten the life span of Kl(-/-) mice. These results demonstrate that Pi has important roles in the aging process, and the blockade of mTORC1 may have therapeutic potential for premature aging-like symptoms associated with hyperphosphatemia.
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Registered trials
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