Figure 3.

Fumarate accumulation, HIF-1α regulation, and glycolysis in renal cells with increased intracellular glucose. The reduced pAMPK enhances NOX4 leading to increased H₂O₂, which reduces fumarate hydratase (FH) levels and then leads to fumarate accumulation. Both increased H2O2 and fumarate contribute to ER stress and thereafter apoptosis. The increased fumarate suppresses HIF-PHD activity resulting in HIF-1α accumulation, which drives the metabolic flux to the glycolytic pathway (eg, through increased LDH) while suppresses oxidative phosphorylation (eg, through reduced PDK and increased PDH) and reduces mitochondrial ${\mathrm{O}}_{2·}^{-}$ HIF-1α also increases levels of glucose transport proteins (eg, GLUT1 and GLUT4) and growth factors (eg, VEGF and TGF-β). Abbreviations: ADP, adenosine diphosphate; G-6-P, glucose 6-phosphate; GLUT1/GLUT4, glucose transporters; LDH, lactate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PHD, prolyl hydroxylase; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor.