Renal Hypoxia in CKD; Pathophysiology and Detecting Methods

Abstract

Chronic kidney disease (CKD) is a major public health problem. Accumulating evidence suggests that CKD aggravates renal hypoxia, and in turn, renal hypoxia accelerates CKD progression. To eliminate this vicious cycle, hypoxia-related therapies, such as hypoxia-inducible factor (HIF) activation (prolyl hydroxylase domain inhibition) or NF-E2-related factor 2 activation, are currently under investigation. Clinical studies have revealed heterogeneity in renal oxygenation; therefore, the detection of patients with more hypoxic kidneys can be used to identify likely responders to hypoxia-oriented therapies. In this review, we provide a detailed description of current hypoxia detection methods. HIF degradation correlates with the intracellular oxygen concentration; thus, methods that can detect intracellular oxygen tension changes are desirable. The use of a microelectrode is a classical technique that is superior in quantitative performance; however, its high invasiveness and the fact that it reflects the extracellular oxygen tension are disadvantages. Pimonidazole protein adduct immunohistochemistry and HIF activation detection reflect intracellular oxygen tension, but these techniques yield qualitative data. Blood oxygen level-dependent magnetic resonance imaging has the advantage of low invasiveness, high quantitative performance, and application in clinical use, but its biggest disadvantage is that it measures only deoxyhemoglobin concentrations. Phosphorescence lifetime measurement is a relatively novel in vivo oxygen sensing technique that has the advantage of being quantitative; however, it has several disadvantages, such as toxicity of the phosphorescent dye and the inability to assess deeper tissues. Understanding the advantages and disadvantages of these hypoxia detection methods will help researchers precisely assess renal hypoxia and develop new therapeutics against renal hypoxia-associated CKD.

Keywords: BOLD-MRI; Nrf2; chronic kidney disease; hypoxia; hypoxia-inducible factor; microelectrode; phosphorescence; pimonidazole.

Figure 1

HIF-α regulation. In the presence of sufficient oxygen, HIF-α is hydroxylated by PHD. Hydroxylated HIF-α is recognized by vHL, which results in proteasomal degradation. In hypoxic conditions or PHD inhibition, HIF-α accumulates in the cytosol and forms a heterodimer with HIF-β, the hypoxia-insensitive unit. The heterodimer translocates to the nucleus and acts as a transcriptional factor that binds to HREs. Abbreviations: HIF, hypoxia-inducible factor; HREs, hypoxia-responsive elements; PHD, prolyl hydroxylase domain; vHL, von Hippel–Lindau disease tumor suppressor.

Figure 2

Nrf2 regulation. Under normal conditions, Nrf2 is recognized by KEAP1, which triggers its proteasomal degradation. In contrast, under stressful conditions, such as increased oxidative stress, Nrf2 recognition by KEAP1 is disturbed, and Nrf2 accumulates in the cytosol and acts as a transcriptional factor via ARE binding. Abbreviations: ARE, anti-oxidant responsive element; KEAP1, Kelch-like ECH-associated protein 1; Nrf2, NF-E2 related factor 2.