ArticleJournal of the American Society of Nephrology : JASN2016
Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury.
Article in Journal of the American Society of Nephrology : JASN, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 60 citations in OpenAlex.
- Immunological mechanisms and novel therapeutic strategies for sepsis‑associated acute kidney injury (Review).International journal of molecular medicine · 2026Review
- Multifaceted mechanisms of unconventional T cells in ischemia-reperfusion injury.Frontiers in immunology · 2026Review
- Investigating the impact of camel whey protein hydrolysate on cyp1a1 and keap1/nrf2 expression in hypoxic stress-affected liver tissue of Oreochromis niloticus.Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology · 2025Article
- High glucose/ChREBP-induced Hif-1α transcriptional activation in CD4Diabetologia · 2025Article
- Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis.Biomedicines · 2025Article
- A Novel 6-bp Repeat Unit (6-bp RU) of the 13th Intron Within the ConservedInternational journal of molecular sciences · 2025Article
- Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation.Science translational medicine · 2024Article
- HIF-2α-dependent induction of miR-29a restrains TNature communications · 2024Article
- Long-term treatment of chronic kidney disease patients with anemia using hypoxia-inducible factor prolyl hydroxylase inhibitors: potential concerns.Pediatric nephrology (Berlin, Germany) · 2024Review
- Mechanisms of HIF-driven immunosuppression in tumour microenvironment.Journal of the Egyptian National Cancer Institute · 2023Review
- Sufentanil inhibits Pin1 to attenuate renal tubular epithelial cell ischemia-reperfusion injury by activating the PI3K/AKT/FOXO1 pathway.International urology and nephrology · 2023Article
- Endotyping COPD: hypoxia-inducible factor-2 as a molecular "switch" between the vascular and airway phenotypes?European respiratory review : an official journal of the European Respiratory Society · 2023Review
- Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways.International journal of molecular sciences · 2023Review
- Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease.Frontiers in pharmacology · 2023Review
- Metabolic signatures of immune cells in chronic kidney disease.Expert reviews in molecular medicine · 2022Review
- Network Pharmacology-Based Exploration of the Therapeutic Mechanisms of Cordyceps cicadae in Renal Ischemia/Reperfusion.Annals of transplantation · 2022Article
- Vitamin C Attenuates Oxidative Stress, Inflammation, and Apoptosis Induced by Acute Hypoxia through the Nrf2/Keap1 Signaling Pathway in Gibel Carp (Antioxidants (Basel, Switzerland) · 2022Article
- Role of T cells in ischemic acute kidney injury and repair.The Korean journal of internal medicine · 2022Review
- Article
- The Role of Purinergic Signaling in Heart Transplantation.Frontiers in immunology · 2022Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Natural killer T (NKT) cells are the major early-acting immune cell type and fundamental immune modulators in ischemia-reperfusion injury (IRI). Because lymphocytes are exposed to various oxygen tensions under pathophysiologic conditions, we hypothesize that hypoxia-inducible factors (HIFs) have roles in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we used Lck-Cre transgenic mice to specifically disrupt HIF-2α in T/NKT cells and found that HIF-2α knockout led to upregulated Fas ligand expression on peripheral NKT cells, but not on conventional T cells. HIF-2α knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated IRI, which could be mitigated by in vivo NK1.1(+) cell depletion or Fas ligand blockade. Compared with wild-type NKT cells, HIF-2α(-/-) NKT cells adoptively transferred to Rag1-knockout mice elicited more severe renal injury, and these mice were not protected by CGS21680, an adenosine A2A receptor agonist. Mechanistically, hypoxia-induced expression of adenosine A2A receptor in NKT cells and CGS21680-induced cAMP production in thymocytes were HIF-2α-dependent. Hydrogen peroxide-induced Fas ligand expression on thymic wild-type NKT cells was significantly attenuated by CGS21680 treatment, but this effect was lost in HIF-2α(-/-) NKT cells. Finally, CGS21680 and LPS, an inducer of HIF-2α in endothelium, synergistically reduced renal IRI substantially, but this effect was absent in Mx1-Cre-induced global HIF-2α-knockout mice. Taken together, our results reveal a hypoxia/HIF-2α/adenosine A2A receptor axis that restricts NKT cell activation when confronted with oxidative stress and thus protects against renal IRI.
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