High glucose and endothelial cell growth: novel effects independent of autocrine TGF-β1 and hyperosmolarity
Abstract
Human endothelial cells were exposed to 5 mM glucose (control), 25 mM (high) glucose, or osmotic control for 72 h. TGF-beta1 production, cell growth, death, and cell cycle progression, and the effects of TGF-beta1 and TGF-beta neutralization on these parameters were studied. High glucose and hyperosmolarity increased endothelial TGF-beta1 secretion (P < 0.0001) and bioactivity (P < 0.0001). However, high glucose had a greater effect on reducing endothelial cell number (P < 0.001) and increasing cellular protein content (P < 0.001) than the osmotic control. TGF-beta antibody only reversed the antiproliferative and hypertrophic effects of high glucose. High glucose altered cell cycle progression and cyclin-dependent kinase inhibitor expression independently of hyperosmolarity. High glucose increased endothelial cell apoptosis (P < 0.01), whereas hyperosmolarity induced endothelial cell necrosis (P < 0.001). TGF-beta antibody did not reverse the apoptotic effects observed with high glucose. Exogenous TGF-beta1 mimicked the increased S phase delay but not endoreduplication observed with high glucose. High glucose altered endothelial cell growth, apoptosis, and cell cycle progression. These growth effects occurred principally via a TGF-beta1 autocrine pathway. In contrast, apoptosis and endoreduplication occurred independently of this cytokine and hyperosmolarity.
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Prolonged elevated glucose can signal as a cell stressor through multiple pathways, including hyperosmolarity, PKC activation, and oxidative damage, likely involving pS-STAT3, as well as pY-STAT3.
“Prolonged elevated glucose could also signal as a cell stressor through multiple pathways, including hyperosmolarity (McGinn et al., 2003), protein kinase C (PKC) activation (Mandarino, 1992), and oxidative damage (Nishikawa et al., 2000), likely involving pS-STAT3, as well as pY-STAT3.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as McGinn et al., 2003
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
- Authors
- McGinn, S., Poronnik, P., King, M., Gallery, E. D. M., & Pollock, C. A.
- Affiliations
- Department of Medicine, Kolling Institute: Renal Research Group, and
- The University of Sydney (AU)
- Royal North Shore Hospital (AU)
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2003-06-01
- Volume
- 284
- Issue
- 6
- Pages
- C1374-C1386
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2123980413
- Cited by
- 63
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 2 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 4
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- high glucose, endothelial cells, TGF-β1, autocrine signaling, hyperosmolarity, endothelial cell growth, apoptosis, necrosis, cell cycle progression, cyclin-dependent kinase inhibitors, endoreduplication, S phase delay, TGF-beta neutralization, diabetic vascular complications
- MeSH terms
- Antibodies, Cell Cycle, Cell Division, Cells, Cultured, Diabetes Mellitus, Endothelium, Vascular, Enzyme Inhibitors, Glucose, Humans, L-Lactate Dehydrogenase, Necrosis, Osmolar Concentration, Proto-Oncogene Proteins, Transforming Growth Factor beta, Cyclins, Apoptosis, Cell Cycle Proteins, Proto-Oncogene Proteins c-bcl-2, Autocrine Communication, Tumor Suppressor Proteins, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, bcl-2-Associated X Protein, Transforming Growth Factor beta1
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