CD36
肾缺血
细胞生物学
趋化因子
肾
树突状细胞
缺氧诱导因子
生物
免疫学
下调和上调
免疫系统
癌症研究
受体
再灌注损伤
医学
缺血
内分泌学
内科学
生物化学
基因
作者
Junwen Qu,Dawei Li,Jingsi Jin,Ning Sun,Jiajin Wu,Chao Yang,Lingling Wu,Shaoyong Zhuang,Haoyu Wu,Ruoyang Chen,Yaofei Ren,Zhong Chen,Ying Liu,Yan Zhang,Xiaodong Yuan,Ming Zhang
出处
期刊:Journal of The American Society of Nephrology
日期:2023-01-01
卷期号:34 (1): 73-87
标识
DOI:10.1681/asn.0000000000000027
摘要
Hypoxia and hypoxia-inducible factors (HIFs) play essential and multiple roles in renal ischemia-reperfusion injury (IRI). Dendritic cells (DCs) comprise a major subpopulation of the immunocytes in the kidney and are key initiators and effectors of the innate immune responses after IRI. The role of HIF-2α in DCs remains unclear in the context of renal IRI.To investigate the importance of HIF-2α in DCs upon renal IRI, we examined the effects of DC-specific HIF-2α ablation in a murine model. Bone marrow-derived DCs (BMDCs) from DC-specific HIF-2α-ablated mice and wild-type mice were used for functional studies and transcriptional profiling.DC-specific ablation of HIF-2α led to hyperactivation of natural killer T (NKT) cells, ultimately exacerbating murine renal IRI. HIF-2α deficiency in DCs triggered IFN-γ and IL-4 production in NKT cells, along with upregulation of type I IFN and chemokine responses that were critical for NKT cell activation. Mechanistically, loss of HIF-2α in DCs promoted their expression of CD36, a scavenger receptor for lipid uptake, increasing cellular lipid accumulation. Furthermore, HIF-2α bound directly to a reverse hypoxia-responsive element (rHRE) in the CD36 promoter. Importantly, CD36 blockade by sulfo-N-succinimidyl oleate (SSO) reduced NKT cell activation and abolished the exacerbation of renal IRI elicited by HIF-2α knockout.Our study reveals a previously unrecognized role of the HIF-2α/CD36 regulatory axis in rewiring DC lipid metabolism under IRI-associated hypoxia. These findings suggest a potential therapeutic target to resolve long-standing obstacles in treatment of this severe complication.
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