Activation of HIF-1α C-terminal transactivation domain promotes tubulointerstitial fibrosis through hexokinase 2-mediated metabolic reprogramming

Abstract

BackgroundThe hypoxia-inducible factor-1α (HIF-1α), a master transcription factor for adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD) and C-terminal (CTAD)]. However, the exact effects of HIF-1α CTAD in chronic kidney disease (CKD) are poorly understood. MethodsHere, two independent mouse models of hypoxia-induced CKD, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy, were established using HIF-1α CTAD knockout (HIF-1α CTAD−/−) mice. Further, hexokinase 2 (HK2) and glycolysis pathway were modulated using genetic and pharmacological interventions, respectively. ResultsWe found that HIF-1α CTAD knockout significantly ameliorated tubulointerstitial fibrosis in two models of hypoxia-induced CKD. Further, we found that tubular HIF-1α CTAD transcriptionally regulated HK2 and subsequently induced proinflammatory and profibrotic tubule phenotype. Mechanistically, HK2 deficiency, which resulted from HIF-1α CTAD knockout, ameliorated tubulointerstitial fibrosis through inhibiting glycolysis. HK2 overexpression markedly promoted tubulointerstitial fibrosis by inducing proinflammatory and profibrotic tubule phenotype in HIF-1α CTAD−/− mice. Finally, glycolysis inhibition with a specific inhibitor significantly ameliorated tubulointerstitial fibrosis and reduced proinflammatory and profibrotic tubule phenotype in CKD mice. ConclusionsActivation of HIF-1α CTAD promotes hypoxia-induced tubulointerstitial fibrosis through hexokinase 2-mediated glycolysis. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of the kidney responses to hypoxia in CKD, providing a promising therapeutic strategy for hypoxia-induced CKD.