ArticleMolecular medicine (Cambridge, Mass.)2023
Nr4a1 promotes renal interstitial fibrosis by regulating the p38 MAPK phosphorylation.
Article in Molecular medicine (Cambridge, Mass.), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 33 citations in OpenAlex.
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- Activating protein kinases to treat diseases: Current understanding and future challenges.Acta pharmaceutica Sinica. B · 2026Review
- The subcellular localization-dependent dual role of NR4A1 in renal fibrosis: mechanisms and therapeutic perspectives.Frontiers in pharmacology · 2026Review
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- TGF-β in chronic kidney disease: a controversy for decades.Frontiers in immunology · 2026Review
- HPDA-based tubule-targeting nanoplatform alleviates oxidative stress and ferroptosis for the reversal of renal interstitial fibrosis.Journal of nanobiotechnology · 2025Article
- Bruceine A protects nuclear receptor 4A1 from ubiquitin-degradation to alleviate mesangial proliferative glomerulonephritis.Signal transduction and targeted therapy · 2025Article
- Mechanisms of Xuefu Zhuyu decoction in treating diabetic kidney disease-induced renal fibrosis: UPLC-Q/TOF-MS, network pharmacology, and experimental validation.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2025Article
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- Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.Signal transduction and targeted therapy · 2025Review
- Vasopressin-Sensitive Aqp2 Regulation Mediated by the TAZ-NR4A1 Axis in Renal Collecting Duct Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Field direction of static magnetic fields influences kidney fibrosis progression through MAPK signaling and cell cycle alteration.Scientific reports · 2025Article
- Post-translational modifications of collagen and its related diseases in metabolic pathways.Acta pharmaceutica Sinica. B · 2025Review
- NR4A1 silencing alleviates high-glucose-stimulated HK-2 cells pyroptosis and fibrosisWorld journal of diabetes · 2025Article
- RNA-Binding Protein Lgals3 , Ferroptosis, and Acute Kidney Injury.Journal of the American Society of Nephrology : JASN · 2025Article
- Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV-2 Infection.Kidney360 · 2025Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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Abstract
backgroundRenal interstitial fibrosis (RIF) is a common pathway to end-stage renal disease regardless of the initial etiology. Currently, the molecular mechanisms for RIF remains not fully elucidated. Nuclear receptor subfamily 4 group A member 1(Nr4a1), a member of the NR4A subfamily of nuclear receptors, is a ligand-activated transcription factor. The role of Nr4a1 in RIF remains largely unknown.
methodsIn this study, we determined the role and action mechanism of Nr4a1 in RIF. We used unilateral ureteral obstruction (UUO) mice and transforming growth factor (TGF)-β1-treated human renal proximal tubular epithelial cells (HK-2 cells) as in vivo and in vitro models of RIF. A specific Nr4a1 agonist Cytosporone B (Csn-B) was applied to activate Nr4a1 both in vivo and in vitro, and Nr4a1 small interfering RNA was applied in vitro. Renal pathological changes were evaluated by hematoxylin and eosin and Masson staining, and the expression of fibrotic proteins including fibronectin (Fn) and collagen-I (Col-I), and phosphorylated p38 MAPK was measure by immunohistochemical staining and western blot analysis.
resultsThe results showed that Nr4a1 was upregulated in UUO mouse kidneys, and was positively correlated with the degree of interstitial kidney injury and the levels of fibrotic proteins. Csn-B treatment aggravated UUO-induced renal interstitial fibrosis, and induced p38 MAPK phosphorylation. In vitro, TGF-β induced Nr4a1 expression, and Nr4a1 downregulation prevented TGF-β1-induced expression of Fn and Col-I and the activation of p38 MAPK. Csn-B induced fibrotic proteins expression and p38 MAPK phosphorylation, and moreover Csn-B induced fibrotic proteins expression was abrogated by treatment with p38 MAPK inhibitor SB203580. We provided further evidence that Csn-B treatment promoted cytoplasmic accumulation of Nr4a1.
conclusionThe findings in the present study indicate that Nr4a1 promotes renal fibrosis potentially through activating p38 MAPK kinase.
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