Aims/hypothesis 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. Methods 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. Results 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 expression, which was dependent on the transcription factor ChREBP. Consistent with results from Hif-1α−/− CD4+ T cells, adoptive transfer of Chrebp−/− CD4+ T cells to wild-type diabetic mice also elicited severe diabetic renal damage. By contrast, Chrebp−/−Ifn-γ−/− CD4+ T cells failed to show nephrotoxic effects. Examination of the Hif-1α promoter identified a ChREBP-binding sequence that mediated transcriptional upregulation of Hif-1α by high glucose. Conclusions/interpretation Our study reveals a previously unrecognised high glucose/ChREBP/Hif-1α transcription axis in CD4+ T cells, which serves as a self-protection mechanism against DKD progression via limiting T helper 1 response. Graphical Abstract

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

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2025年1月30日

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Shaoyong Zhuang,
Nan Sun,
Junwen Qu,
Qian Chen,
Conghui Han,
Hao Yin,
Xiaodong Yuan,
Ming Zhang

摘要

Aims/hypothesis

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.

Methods

Lck-Cre⁺Hif1a^loxp/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.

Results

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 expression, which was dependent on the transcription factor ChREBP. Consistent with results from Hif-1α^−/− CD4⁺ T cells, adoptive transfer of Chrebp^−/− CD4⁺ T cells to wild-type diabetic mice also elicited severe diabetic renal damage. By contrast, Chrebp^−/−Ifn-γ^−/− CD4⁺ T cells failed to show nephrotoxic effects. Examination of the Hif-1α promoter identified a ChREBP-binding sequence that mediated transcriptional upregulation of Hif-1α by high glucose.

Conclusions/interpretation

Our study reveals a previously unrecognised high glucose/ChREBP/Hif-1α transcription axis in CD4⁺ T cells, which serves as a self-protection mechanism against DKD progression via limiting T helper 1 response.

Graphical Abstract

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

摘要

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