Hypoxia-Inducible Factor 2α Attenuates Renal Ischemia-Reperfusion Injury by Suppressing CD36-Mediated Lipid Accumulation in Dendritic Cells in a Mouse Model

Abstract

Significance Statement Hypoxia is a hallmark of renal ischemia-reperfusion injury (IRI) and serves as an essential regulator of innate immune responses during this process, although the mechanisms of this regulation remain unclear. Here, we showed in a murine model that HIF-2α knockout in dendritic cells (DCs) exacerbated renal IRI through activation of natural killer T cells. Mechanistically, HIF-2α deficiency upregulated CD36 expression of DCs, leading to cellular lipid accumulation. Pharmacologic inhibition of CD36 in DCs resulted in renoprotection by reducing lipid content and suppressing natural killer T cell activation. Our study strongly suggests that targeting the HIF-2α/CD36 regulatory axis may be a strategy for alleviating renal IRI. 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-2α in DCs remains unclear in the context of renal IRI. Methods 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. Results 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. Conclusions 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.