Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

Abstract

The pathogenesis of chronic kidney disease (CKD) is complex and apparently multifactorial. Hypoxia or decrease in oxygen supply in kidney tissues has been implicated in CKD. Hypoxia inducible factors (HIF) are a small family of transcription factors that are mainly responsive to hypoxia and mediate hypoxic response. HIF plays a critical role in renal fibrosis during CKD through the modulation of gene transcription, crosstalk with multiple signaling pathways, epithelial-mesenchymal transition, and epigenetic regulation. Moreover, HIF also contributes to the development of various pathological conditions associated with CKD, such as anemia, inflammation, aberrant angiogenesis, and vascular calcification. Treatments targeting HIF and related signaling pathways for CKD therapy are being developed with promising clinical benefits, especially for anemia. This review presents an updated analysis of hypoxia response, HIF, and their associated signaling network involved in the pathogenesis of CKD.

Keywords: CKD; HIF; fibrosis; hypoxia.

Figure 1

Schematic diagram of HIF regulation in CKD. In normoxia or the presence of O₂, HIF-α is hydroxylated by prolyl hydroxylase domain (PHD) resulting in its binding of von Hippel Lindau protein (pVHL)-E3-ubiquitin ligase complex, poly-ubiquitination, and consequent proteosomal degradation. In hypoxia or the absence of O₂, PHD-mediated hydroxylation is inhibited, leading to HIF-α stabilization and accumulation. HIF-α dimerizes with HIF-β to form functional HIF that translocates to nucleus to activate down-stream gene transcription. Hypoxia is a feature in kidney tissues in CKD that activates HIF, which integrates multiple signaling networks to induce renal fibrosis. In addition, tissue hypoxia and HIF contribute to other CKD-associated pathogenic processes including anemia, angiogenesis, inflammation, and vascular calcification. Abbreviations: Epithelial-Meshenchymal Transition (EMT), Erythropoietin (EPO), vascular endothelial growth factor (VEGF), transforming growth factor (TGF).