ArticleJournal of the American Society of Nephrology : JASN2012
Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4.
Article in Journal of the American Society of Nephrology : JASN, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 263 papers, 1 of them a synthesis that pooled it.
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Who cites it
263 citing papers in PubMed, 1 synthesis or guideline pooled it, 424 citations in OpenAlex.
- Emerging trends and focus of Toll-like receptors in kidney diseases: a 20-year bibliometric analysis.Frontiers in medicine · 2025Pooled it
- Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms.Scientific reports · 2016Trial
- Complement activation and fibrinolysis dysregulation drive contrast-induced acute kidney injury: a 4D proteomics rat study.Renal failure · 2026Article
- TLR2 inhibition attenuates NET-driven inflammation and restenosis during poly-lactic acid bioresorbable scaffold degradation.Bioactive materials · 2026Article
- Histone neutralization protects the ischemic brain against the consequences of stroke-associated pneumonia.Acta neuropathologica · 2026Article
- Targeting biglycan-TLR2/TLR4 interaction with synthetic peptides mitigates inflammation and ameliorates renal function in ischemia-reperfusion injury.Cellular & molecular biology letters · 2026Article
- SMOC2 promotes partial epithelial-mesenchymal transition and maladaptive repair in renal tubular epithelial cells.JCI insight · 2026Article
- Review
- Role of post-translational modifications in modulating histone reactivity in the extracellular environment.Biochemical Society transactions · 2026Review
- Predictive performance of kinetic eGFR, midregional proadrenomedullin, and H3.1 nucleosomes for acute kidney disease in sepsis: a secondary analysis of a large multicentre randomized controlled trial.Journal of intensive care · 2026Article
- IRF1-mediated sensing of oxidized mitochondrial DNA drives macrophage PANoptosis in lung ischemia-reperfusion injury.Apoptosis : an international journal on programmed cell death · 2026Article
- Review
- Chinese Herb-Induced Type II Crescentic Glomerulonephritis: A Case Report of Four Patients.Kidney medicine · 2026Article
- Molecular mechanisms of acute inflammation: systemic responses and kidney-specific pathophysiology.Function (Oxford, England) · 2026Review
- Neutrophil extracellular traps and acute kidney injury: a narrative review.Frontiers in immunology · 2026Review
- Neutrophil extracellular traps in the animal model of adenine-induced chronic kidney disease.PloS one · 2026Article
- Organ Crosstalk During Injury: Mechanisms of Lung-Kidney Interaction in Critical Illness.Comprehensive Physiology · 2025Review
- Myeloid Cells in Acute Kidney Injury.Seminars in nephrology · 2025Review
- Preclinical evaluation of sodium copper chlorophyllin: safety, pharmacokinetics, and therapeutic potential in breast cancer chemotherapy and cyclophosphamide-induced bladder toxicity.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Cardioprotective effects of the extracellular chaperone clusterin in acute myocardial infarction.European journal of clinical investigation · 2025Article
203 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-κB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.
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Registered trials
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 OpenQuestion graph.