ArticleJournal of molecular cell biology2019
p53 upregulated by HIF-1α promotes hypoxia-induced G2/M arrest and renal fibrosis in vitro and in vivo.
Article in Journal of molecular cell biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 71 citations in OpenAlex.
- The hemodynamic cost of intermittent hemodialysis and systemic organ stunning.Renal failure · 2026Review
- Infection and α-ketoglutarate/oxygen inhibition converge to CDC20 to promote cancer cell aneuploidy.Signal transduction and targeted therapy · 2026Article
- Antifibrotic Effects of Yi-Qi-Jian-Pi-Xiao-Yu Formula in Kidney via HIF1A-Driven M1 Macrophage Polarization.Phytochemical analysis : PCA · 2026Article
- The Positive Feedback Loop of Hypoxia-Inducible Factor-1 α /miR-295/Factor Inhibiting Hypoxia-Inducible Factor-1 in Hyperuricemic Nephropathy.Kidney360 · 2026Article
- The Ubiquitin-Specific Protease Family: Master Regulators of Renal Fibrosis Pathogenesis and Therapeutic Targets.International journal of molecular sciences · 2026Review
- Plasma proteomics identify novel biomarkers and dynamic patterns of biological aging.Journal of advanced research · 2026Article
- The molecular mechanisms and therapeutic potential of p53 in kidney injury repair: a perspective on the p53alpha/delta133p53alpha signaling axis.Renal failure · 2025Review
- Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity.Molecular diversity · 2025Article
- Targeting hypoxia-inducible factor 1α in chronic graft-versus-host disease to enhance graft-versus-leukemia responses: implications for nanotherapeutics.Frontiers in immunology · 2025Review
- The molecular interplay among gut dysbiosis, adipose tissue, and metabolite-derived damage-associated molecular patterns in metainflammation and atherogenesis.Frontiers in immunology · 2025Review
- Molecular signaling and clinical implications in the human aging-cancer cycle.Seminars in cancer biology · 2024Review
- Epithelial-mesenchymal transition in tissue repair and degeneration.Nature reviews. Molecular cell biology · 2024Review
- Targeting tumor suppressor p53 for organ fibrosis therapy.Cell death & disease · 2024Review
- Molecular mechanism of human ISG20L2 for the ITS1 cleavage in the processing of 18S precursor ribosomal RNA.Nucleic acids research · 2024Article
- From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease.International journal of molecular sciences · 2024Review
- Knockdown of MRPL35 promotes cell apoptosis and inhibits cell proliferation in non-small-cell lung cancer.BMC pulmonary medicine · 2023Article
- Research progress on the mechanism of renal interstitial fibrosis in obstructive nephropathy.Heliyon · 2023Review
- p53 and Myofibroblast Apoptosis in Organ Fibrosis.International journal of molecular sciences · 2023Review
- The long noncoding RNA Meg3 mediates TLR4-induced inflammation in experimental obstructive nephropathy.Clinical science (London, England : 1979) · 2023Article
- Nephroprotective mechanisms of Rhizoma Chuanxiong and Radix et Rhizoma Rhei against acute renal injury and renal fibrosis based on network pharmacology and experimental validation.Frontiers in pharmacology · 2023Article
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypoxia plays an important role in the genesis and progression of renal fibrosis. The underlying mechanisms, however, have not been sufficiently elucidated. We examined the role of p53 in hypoxia-induced renal fibrosis in cell culture (human and rat renal tubular epithelial cells) and a mouse unilateral ureteral obstruction (UUO) model. Cell cycle of tubular cells was determined by flow cytometry, and the expression of profibrogenic factors was determined by RT-PCR, immunohistochemistry, and western blotting. Chromatin immunoprecipitation and luciferase reporter experiments were performed to explore the effect of HIF-1α on p53 expression. We showed that, in hypoxic tubular cells, p53 upregulation suppressed the expression of CDK1 and cyclins B1 and D1, leading to cell cycle (G2/M) arrest (or delay) and higher expression of TGF-β, CTGF, collagens, and fibronectin. p53 suppression by siRNA or by a specific p53 inhibitor (PIF-α) triggered opposite effects preventing the G2/M arrest and profibrotic changes. In vivo experiments in the UUO model revealed similar antifibrotic results following intraperitoneal administration of PIF-α (2.2 mg/kg). Using gain-of-function, loss-of-function, and luciferase assays, we further identified an HRE3 region on the p53 promoter as the HIF-1α-binding site. The HIF-1α-HRE3 binding resulted in a sharp transcriptional activation of p53. Collectively, we show the presence of a hypoxia-activated, p53-responsive profibrogenic pathway in the kidney. During hypoxia, p53 upregulation induced by HIF-1α suppresses cell cycle progression, leading to the accumulation of G2/M cells, and activates profibrotic TGF-β and CTGF-mediated signaling pathways, causing extracellular matrix production and renal fibrosis.
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