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

Abstract

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.

Advances in understanding of dendritic cell in the pathogenesis of acute kidney injury

“…Previous studies have shown that DC activation in RIRI is accompanied by an increase in HIF-1a protein levels, and knockdown of HIF-1a significantly inhibits DC maturation and impairs the stimulation of allogeneic T cells (80, 81). In contrast, a recent study showed that HIF-2a deficiency in DCs upregulated CD36 expression in DCs, leading to cellular lipid accumulation, causing the overactivation of natural killer T (NKT) cells the production of IFN-g and IL4, and ultimately exacerbating RIRI in mice (82). This finding suggests that hypoxia plays a crucial role in DC activation, and targeting and regulating HIF-1a or HIF-2a expression could be a potential therapeutic strategy for RIRI.…”