ArticleGastroenterology2015
Rapamycin Inhibition of mTOR Reduces Levels of the Na+/H+ Exchanger 3 in Intestines of Mice and Humans, Leading to Diarrhea.
Article in Gastroenterology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 38 citations in OpenAlex.
- Fecal metagenome and plasma metabolome analyses reveal changes in gut microbiota composition and plasma metabolites in rats with abemaciclib-induced diarrhea.BMC gastroenterology · 2026Article
- Optimizing clinical monitoring and management guidelines for capivasertib in HR-positive/HER2-negative advanced breast cancer: expert opinion.NPJ breast cancer · 2025Review
- Autophagy Regulates Putative Anion Transporter 1 Expression in Intestinal Epithelial Cells.Journal of cellular and molecular medicine · 2025Article
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- Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas.Cells · 2023Review
- G Protein-Coupled Receptor 37L1 Modulates Epigenetic Changes in Human Renal Proximal Tubule Cells.International journal of molecular sciences · 2022Article
- Article
- mTORC2 suppresses cell death induced by hypo-osmotic stress by promoting sphingomyelin transport.The Journal of cell biology · 2022Article
- The use of non-model Drosophila species to study natural variation in TOR pathway signaling.PloS one · 2022Article
- Ligustrazine protects against chronic hypertensive glaucoma in rats by inhibiting autophagy via the PI3K-Akt/mTOR pathway.Molecular vision · 2021Article
- Premises among SARS-CoV-2, dysbiosis and diarrhea: Walking through the ACE2/mTOR/autophagy route.Medical hypotheses · 2020Article
- Metabolic and immunologic control of intestinal cell function by mTOR.International immunology · 2020Review
- Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- EGFR as a Negative Regulatory Protein Adjusts the Activity and Mobility of NHE3 in the Cell Membrane of IPEC-J2 Cells With TGEV Infection.Frontiers in microbiology · 2018Article
- Production of interleukin-1β related to mammalian target of rapamycin/Toll-like receptor 4 signaling pathway duringInternational journal of ophthalmology · 2018Article
- Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.JCI insight · 2017Article
- Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy.Stem cell research & therapy · 2017Article
- Intestinal Epithelial-Specific mTORC1 Activation Enhances Intestinal Adaptation After Small Bowel Resection.Cellular and molecular gastroenterology and hepatology · 2017Article
- Pathophysiology of Intestinal NaCellular and molecular gastroenterology and hepatology · 2017Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND &
aimsThe immunosuppressant rapamycin frequently causes noninfectious diarrhea in organ transplant recipients. We investigated the mechanisms of this process.
methodsWe performed a retrospective analysis of renal transplant recipients treated with rapamycin from 2003 through 2010 at Albany Medical College, collecting data on serum levels of rapamycin. Levels of the Na+/H+ exchanger 3 (NHE3) were measured in human ileal biopsy specimens from patients who did and did not receive rapamycin (controls), in ileum tissues from rats or mice given rapamycin, and in mice with intestine-specific disruption of mammalian target of rapamycin (Mtor) (mTOR(f/f):Villin-cre mice) or Atg7 (Atg7(flox/flox); Villin-Cre). Exchange activity and intestinal water absorption were measured using a pH-sensitive dye and small intestine perfusion, respectively.
resultsEpisodes of noninfectious diarrhea occurred in organ recipients after increases in serum levels of rapamycin. The expression of NHE3 was reduced in the ileal brush border of patients with diarrhea. In rats and mice, continuous administration of low doses of rapamycin reduced levels of NHE3 in intestinal tissues; this effect was not observed in mice with intestinal deletion of ATG7, indicating that autophagy is required for the reduction. Administration of single high doses of rapamycin to mice, to model the spikes in rapamycin levels that occur in patients with severe diarrheal episodes, resulted in reduced phosphorylation of S6 and AKT in ileal tissues, indicating inhibition of the mTOR complex (mTORC1 and mTORC2). The intestines of mice with intestine-specific deletion of mTOR were dilated and contained large amounts of liquid stools; they also had reduced levels of total NHE3 and NHERF1 compared with control mice. We observed a significant reduction in Na(+)/H(+) exchange activity in ileum tissues from these mice.
conclusionsRapamycin inhibition of mTOR reduces levels of NHE3 and Na(+)/H(+) exchange activity in intestinal tissues of patients and rodents. This process appears to require the autophagic activity mediated by ATG7. Loss of mTOR regulation of NHE3 could mediate the development of diarrhea in patients undergoing rapamycin therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.