High glucose/ChREBP-induced Hif-1α transcriptional activation in CD4+ T cells reduces the risk of diabetic kidney disease by inhibiting the Th1 response

作者：Shaoyong Zhuang, Nan Sun, Junwen Qu, Qian Chen, Conghui Han, Hao Yin, Xiaodong Yuan, Ming Zhang · 发表于：Diabetologia · 年份：2025 · DOI：10.1007/s00125-024-06354-7 · 被引用次数：10 · 研究领域：Renal Diseases and Glomerulopathies、Cholesterol and Lipid Metabolism、Lipid metabolism and disorders

Diabetic kidney disease (DKD) features intrarenal inflammation, in which T cells play a part. Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor regulating cellular responses to hypoxia, is reportedly involved in the course of inflammation. The role of HIF-1α in DKD has been investigated, but the conclusions are controversial so far. We report a previously unrecognised high glucose/carbohydrate response element binding protein (ChREBP)/Hif-1α transcription axis in CD4+ T cells. Lck-Cre+Hif1aloxp/loxp (Hif-1α−/−) mice were generated to explore the role of T cell HIF-1α in the pathogenesis of DKD. CD4+ T cells sorted from T cell-specific Hif-1α-ablated mice and wild-type mice were used for functional studies and transcriptional profiling. In this study, we used Lck-Cre transgenic mice to specifically disrupt Hif-1α in T cells and found that ablation of Hif-1α greatly accelerated the progression of DKD in a streptozocin-induced model of diabetes. Adoptive transfer of splenic CD4+ T cells from Hif-1α−/− mice rather than wild-type controls to diabetic mice elicited severe renal damage. Compared with wild-type controls, Hif-1α knockout markedly promoted IFN-γ secretion by CD4+ T cells in response to high glucose. Additional Ifn-γ ablation negated the effect of Hif-1α knockout on DKD progression. Mechanistically, the background Hif-1α mRNA synthesis rate in resting T cells was very low, but culture of T cells under high glucose led to significantly promoted Hif-1α expr...