ArticleThe American journal of pathology2011
Epac1-mediated, high glucose-induced renal proximal tubular cells hypertrophy via the Akt/p21 pathway.
Article in The American journal of pathology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- Linagliptin increases the expression of LRP2 independent of Nrf2 in streptozotocin-induced diabetic mice.Journal of diabetes investigation · 2026Article
- Multifaceted roles of Epac signaling in renal functions.The Biochemical journal · 2025Review
- Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription.Nature communications · 2023Article
- Upregulation of Epac1 Promotes Pericyte Loss by Inducing Mitochondrial Fission, Reactive Oxygen Species Production, and Apoptosis.Investigative ophthalmology & visual science · 2023Article
- Epac: A Promising Therapeutic Target for Vascular Diseases: A Review.Frontiers in pharmacology · 2022Review
- Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells.Scientific reports · 2021Article
- Review
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- The cellular selection between apoptosis and autophagy: roles of vitamin D, glucose and immune response in diabetic nephropathy.Endocrine · 2017Article
- Renoprotective Effects of Aldose Reductase Inhibitor Epalrestat against High Glucose-Induced Cellular Injury.BioMed research international · 2017Article
- Epac1 interacts with importin β1 and controls neurite outgrowth independently of cAMP and Rap1.Scientific reports · 2016Article
- p66Shc: A novel biomarker of tubular oxidative injury in patients with diabetic nephropathy.Scientific reports · 2016Article
- Epac1 knockdown inhibits the proliferation of ovarian cancer cells by inactivating AKT/Cyclin D1/CDK4 pathway in vitro and in vivo.Medical oncology (Northwood, London, England) · 2016Article
- Involvement of Histone Lysine Methylation in p21 Gene Expression in Rat Kidney In Vivo and Rat Mesangial Cells In Vitro under Diabetic Conditions.Journal of diabetes research · 2016Article
- Review
- Modulation of angiotensin II-induced inflammatory cytokines by the Epac1-Rap1A-NHE3 pathway: implications in renal tubular pathobiology.American journal of physiology. Renal physiology · 2014Article
- Article
- Role of guanine-nucleotide exchange factor Epac in renal physiology and pathophysiology.American journal of physiology. Renal physiology · 2013Review
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
The mechanisms involved in tubular hypertrophy in diabetic nephropathy are unclear. We investigated the role of exchange protein activated by cAMP 1(Epac1), which activates Rap-family G proteins in cellular hypertrophy. Epac1 is expressed in heart, renal tubules, and in the HK-2 cell line. In diabetic mice, increased Epac1 expression was observed, and under high glucose ambience (HGA), HK-2 cells also exhibited increased Epac1 expression. We isolated a 1614-bp DNA fragment upstream of the initiation codon of Epac1 gene, inclusive of glucose response elements (GREs). HK-2 or COS7 cells transfected with the Epac1 promoter revealed a dose-dependent increase in its activity under HGA. Mutations in GRE motifs resulted in decreased promoter activity. HK-2 cells exhibited a hypertrophic response and increased protein synthesis under HGA, which was reduced by Epac1-siRNA or -mutants, whereas the use of a protein kinase A inhibitor had minimal effect. Epac1 transfection led to cellular hypertrophy and increased protein synthesis, which was accentuated by HGA. HGA increased the proportion of cells in the G0/G1 cell-cycle phase, and the expression of pAkt and the cyclin-dependent kinase inhibitors p21 and p27 was increased while the activity of cyclin-dependent kinase 4 decreased. These effects were reversed following transfection of cells with Epac1-siRNA or -mutants. These data suggest that HGA increases GRE-dependent Epac1 transcription, leading to cell cycle arrest and instigation of cellular hypertrophy.
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