Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis
<b>Background:</b> Anti-glomerular basement membrane (anti-GBM) nephritis is mediated by autoantibodies and may progress to end-stage renal disease. Although its pathogenesis is not completely understood, dendritic cells (DCs) have been reported to play an important role in this process....
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2025-04-01
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| author | Jiayi Miao Junwen Qu Dawei Li Ming Zhang |
| author_facet | Jiayi Miao Junwen Qu Dawei Li Ming Zhang |
| author_sort | Jiayi Miao |
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| description | <b>Background:</b> Anti-glomerular basement membrane (anti-GBM) nephritis is mediated by autoantibodies and may progress to end-stage renal disease. Although its pathogenesis is not completely understood, dendritic cells (DCs) have been reported to play an important role in this process. Hypoxia-inducible factor-2α (HIF-2α) has been reported to have a regulatory effect on DCs under hypoxic conditions, while no research has investigated its role in autoimmune nephritis. <b>Methods:</b> Anti-GBM nephritis was induced in CD11c-specific HIF-2α-deficient and WT mice using nephrotoxic serum (NTS). All mice were divided into four groups: (i) WT+PBS, (ii) CD11c-Cre<sup>+</sup> Hif2α<sup>fl/fl</sup>+PBS, (iii) WT+NTS and (iv) CD11c-Cre<sup>+</sup> Hif2α<sup>fl/fl</sup>+NTS. Seven days after induction, renal function, immune cell infiltration and the expression levels of genes in the renal cortex were assessed in each group. <b>Results:</b> On day 7, the levels of serum creatinine and blood urea nitrogen and the urine albumin-to-creatinine ratio were lower for mice with DC-specific deletion of HIF-2α compared with their WT counterparts (<i>p</i> < 0.05). Histopathological analysis showed that there was less crescent formation in the renal cortex with conditional HIF-2α knockout, and the infiltration of DCs and macrophages was also suppressed (<i>p</i> < 0.05). Genes related to antigen processing and presentation were found to be expressed differentially between the two groups, and the activation of the MAPK pathway was affected (<i>p</i> < 0.05). Western blot analysis validated that HIF-2α knockout inhibited the phosphorylation of p38 MAPK (<i>p</i> < 0.05). <b>Conclusions:</b> In this study, we observed a pro-inflammatory effect of HIF-2α in DCs in early anti-GBM nephritis, and the results suggested a regulating effect of HIF-2α on p38 MAPK pathways. |
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| spelling | doaj-art-1eb9bf397cb8491a857a3a5f2e7cd3722025-08-20T02:17:20ZengMDPI AGBiomedicines2227-90592025-04-0113488810.3390/biomedicines13040888Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane NephritisJiayi Miao0Junwen Qu1Dawei Li2Ming Zhang3Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, ChinaDepartment of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, ChinaDepartment of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, ChinaDepartment of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China<b>Background:</b> Anti-glomerular basement membrane (anti-GBM) nephritis is mediated by autoantibodies and may progress to end-stage renal disease. Although its pathogenesis is not completely understood, dendritic cells (DCs) have been reported to play an important role in this process. Hypoxia-inducible factor-2α (HIF-2α) has been reported to have a regulatory effect on DCs under hypoxic conditions, while no research has investigated its role in autoimmune nephritis. <b>Methods:</b> Anti-GBM nephritis was induced in CD11c-specific HIF-2α-deficient and WT mice using nephrotoxic serum (NTS). All mice were divided into four groups: (i) WT+PBS, (ii) CD11c-Cre<sup>+</sup> Hif2α<sup>fl/fl</sup>+PBS, (iii) WT+NTS and (iv) CD11c-Cre<sup>+</sup> Hif2α<sup>fl/fl</sup>+NTS. Seven days after induction, renal function, immune cell infiltration and the expression levels of genes in the renal cortex were assessed in each group. <b>Results:</b> On day 7, the levels of serum creatinine and blood urea nitrogen and the urine albumin-to-creatinine ratio were lower for mice with DC-specific deletion of HIF-2α compared with their WT counterparts (<i>p</i> < 0.05). Histopathological analysis showed that there was less crescent formation in the renal cortex with conditional HIF-2α knockout, and the infiltration of DCs and macrophages was also suppressed (<i>p</i> < 0.05). Genes related to antigen processing and presentation were found to be expressed differentially between the two groups, and the activation of the MAPK pathway was affected (<i>p</i> < 0.05). Western blot analysis validated that HIF-2α knockout inhibited the phosphorylation of p38 MAPK (<i>p</i> < 0.05). <b>Conclusions:</b> In this study, we observed a pro-inflammatory effect of HIF-2α in DCs in early anti-GBM nephritis, and the results suggested a regulating effect of HIF-2α on p38 MAPK pathways.https://www.mdpi.com/2227-9059/13/4/888anti-GBM glomerulonephritisdendritic cellhypoxia-inducible factor-2αp38 mitogen-activated protein kinase |
| spellingShingle | Jiayi Miao Junwen Qu Dawei Li Ming Zhang Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis Biomedicines anti-GBM glomerulonephritis dendritic cell hypoxia-inducible factor-2α p38 mitogen-activated protein kinase |
| title | Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis |
| title_full | Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis |
| title_fullStr | Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis |
| title_full_unstemmed | Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis |
| title_short | Deletion of HIF-2α in Dendritic Cells Attenuates Anti-Glomerular Basement Membrane Nephritis |
| title_sort | deletion of hif 2α in dendritic cells attenuates anti glomerular basement membrane nephritis |
| topic | anti-GBM glomerulonephritis dendritic cell hypoxia-inducible factor-2α p38 mitogen-activated protein kinase |
| url | https://www.mdpi.com/2227-9059/13/4/888 |
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