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

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.