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Background 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-2a in DCs remains unclear in the context of renal IRI.Methods To investigate the importance of HIF-2a in DCs upon renal IRI, we examined the effects of DC-specific HIF-2a ablation in a murine model. Bone marrow-derived DCs (BMDCs) from DC-specific HIF-2a-ablated mice and wild-type mice were used for functional studies and transcriptional profiling.Results DC-specific ablation of HIF-2a led to hyperactivation of natural killer T (NKT) cells, ultimately exacerbating murine renal IRI. HIF-2a deficiency in DCs triggered IFN-g 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-2a in DCs promoted their expression of CD36, a scavenger receptor for lipid uptake, increasing cellular lipid accumulation. Furthermore, HIF-2a 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-2a knockout.Conclusions Our study reveals a previously unrecognized role of the HIF-2a/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.