PFKFB2-Induced Glycolysis and Ferroptosis in Diabetic Nephropathy by HIF-1α

In recent years, the prevalence of diabetic nephropathy (DN) has been increasing year by year. Here, this experiment investigated the effects of PFKFB2 in DN and its molecular mechanisms of DN. DN mice were fed a high-fat diet for 12 weeks, and then injected with STZ. DN mice were transfected with negative or sh-DPP9 lentivirus using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA). Human proximal tubular HK-2 cells stimulated with 20 mmol/L d-glucose. Analysis revealed a significant downregulation of PFKFB2 expression in DN patients. PFKFB2 was expression in renal cell of DN model using single-cell RNA sequencing. Sh-PFKFB2 aggravated DN in mice model. PFKFB2 up-regulation reduced oxidative stress and glycolysis in model of DN. The inhibition of PFKFB2 aggravated mitochondria-dependent ferroptosis in model of DN. Ferroptosis inhibitor reduced the effects of PFKFB2 down-regulation in mitochondria-dependent ferroptosis in model of DN. PFKFB2 suppressed HIF-1α expression in model of DN by the inhibition of HIF-1α ubiquitination. HIF-1α inhibitor reduced the effects of PFKFB2 down-regulation in mitochondria-dependent ferroptosis in model of DN. In conclusion, PFKFB2 reduced oxidative stress and glycolysis of DN through the inhibition of HIF-1α signaling pathway by the induction of Nrf2 ubiquitination, further elucidating the role of PFKFB2 regulated mitochondrial ROS-induced ferroptosis for DN. Targeting PFKFB2 is thus a potentially effective therapeutic strategy for DN.