Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis

Abstract

Renal fibrosis is the result of renal tissue damage and repair response disorders. If fibrosis is not effectively blocked, it causes loss of renal function, leading to chronic renal failure. Metabolic reprogramming, which promotes cell proliferation by regulating cellular energy metabolism, is considered a unique tumor cell marker. The transition from oxidative phosphorylation to aerobic glycolysis is a major feature of renal fibrosis. Hypoxia-inducible factor-1 α (HIF-1α), a vital transcription factor, senses oxygen status, induces adaptive changes in cell metabolism, and plays an important role in renal fibrosis and glucose metabolism. This review focuses on the regulation of proteins related to aerobic glycolysis by HIF-1α and attempts to elucidate the possible regulatory mechanism underlying the effects of HIF-1α on glucose metabolism during renal fibrosis, aiming to provide new ideas for targeted metabolic pathway intervention in renal fibrosis.

Keywords: aerobic glycolysis; hypoxia-inducible factor-1α; metabolic reprogramming; oxidative phosphorylation; renal fibrosis.

Figure 1

HIF-1α expression increases under hypoxia, which promoted renal fibrosis through the following aspects: Stimulating the secretion of interleukin-1β (IL-1 β) and tumor necrosis factor-α (TNF-α), and increasing the inflammatory reaction, upregulation of the epithelial cell marker E-cadherin and downregulation of the mesenchymal marker vimentin promote EMT, enhance pro-fibrosis cytokines such as plasminogen activator inhibitor 1 (PAI-1) and tissue inhibitor of metalloproteinase (TIMPs), and regulate fibrosis-related signaling pathways such as TGF-β/Smads signaling.

Figure 2

Glucose transport into cells through GLUT and decompose into pyruvate by a series of glycolytic enzymes such as HK2, PFK1 and PKM2. PDC catalyzes the conversion of pyruvate into acetyl-CoA, enters TCA cycle, generates NADH and FADH2, and then enters ETC to produce ATP. Under hypoxia, pyruvate is activated by LDHA to generate lactate. HIF-1α can increase glycolysis flux by up-regulating HK2, PFK1 and PKM2. At the same time, increasing the levels of PDK1 and LDHA inhibited pyruvate from entering TCA cycle.

Figure 3

With the stimulation of external factors such as growth factor, cytokines and hormone, PI3K/Akt/mTOR signaling pathway is activated, which can promote HIF-1α transcription activity, increase the transcription of glycolytic genes, up-regulate the levels of PDK1 and LDHA, and then increase glycolysis while inhibit OXPHOS.