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Review
. 2022 Oct 28;27(21):7318.
doi: 10.3390/molecules27217318.

The Role of Hypoxia-Inducible Factor-1 Alpha in Renal Disease

Huixia Liu  1 , Yujuan Li  1 , Jing Xiong  1
Affiliations
Review

The Role of Hypoxia-Inducible Factor-1 Alpha in Renal Disease

Huixia Liu et al. Molecules. .

Abstract

Partial pressure of oxygen (pO2) in the kidney is maintained at a relatively stable level by a unique and complex functional interplay between renal blood flow, glomerular filtration rate (GFR), oxygen consumption, and arteriovenous oxygen shunting. The vulnerability of this interaction renders the kidney vulnerable to hypoxic injury, leading to different renal diseases. Hypoxia has long been recognized as an important factor in the pathogenesis of acute kidney injury (AKI), especially renal ischemia/reperfusion injury. Accumulating evidence suggests that hypoxia also plays an important role in the pathogenesis and progression of chronic kidney disease (CKD) and CKD-related complications, such as anemia, cardiovascular events, and sarcopenia. In addition, renal cancer is linked to the deregulation of hypoxia pathways. Renal cancer utilizes various molecular pathways to respond and adapt to changes in renal oxygenation. Particularly, hypoxia-inducible factor (HIF) (including HIF-1, 2, 3) has been shown to be activated in renal disease and plays a major role in the protective response to hypoxia. HIF-1 is a heterodimer that is composed of an oxygen-regulated HIF-1α subunit and a constitutively expressed HIF-1β subunit. In renal diseases, the critical characteristic of HIF-1α is protective, but it also has a negative effect, such as in sarcopenia. This review summarizes the mechanisms of HIF-1α regulation in renal disease.

Keywords: complications; diabetic nephropathy; hypoxia-inducible factor-1α; renal cancer; renal ischemia/reperfusion injury.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Under normoxia, HIF-1α is rapidly degraded when it is hydroxylated at two proline residues within the oxygen-dependent degradation domain by prolyl hydroxylase domain (PHD) proteins. It is subsequently ubiquitinated by the E3 ubiquitin ligase activity of the von Hippel-Lindau tumor suppressor protein (pVHL), thereby targeting HIF-1α for degradation by the proteasome. Under hypoxia, HIF-1α transfers to the nucleus and heterodimerizes with HIF-1β. The HIF-1 dimer subsequently binds to the hypoxia-response element sites on the DNA to initiate the expression of more than 100 genes involved in hypoxia adaptation.
Figure 2
Figure 2
Mitochondrial dysfunction, induction of inflammation, apoptosis, autophagy, necroptosis, angiogenesis and ROS are the major factors in the pathogenesis of RIRI, and HIF−1α can protect against the kidney injury caused by RIRI through the above mechanisms (↑: elevated expression; ↓: decreased expression).
Figure 3
Figure 3
Mitochondrial dysfunction, lipid peroxidation, oxidative stress, ROS, machrophages activation, glycolysis, and the induction of inflammation are the major factors in the pathogenesis of DN, and HIF-1α can protect and aggravate the kidney injury caused by DN through the above mechanisms(↑: elevated expression).
Figure 4
Figure 4
HIF-1α regulates EPO gene in the kidney and liver and also regulates iron metabolism by stimulating DCYTB and DMT1 expression. Inhibition of HIF-PHD leads to increased EPO production, better iron absorption, and amelioration of anemia in CKD. Under hypoxia, HIF signaling affects the cardiac development, metabolic response, heart ischemia and atherosclerosis to CVD in myriad ways. And HIF-1α plays a dual role in sarcopenia through the mechanisms described above (↑: elevated expression; ↓: decreased expression).
Figure 5
Figure 5
ROS removing, mitochondrial metabolism, cell signaling activation are regulated by HIF-1α, which can regulate tumor occurrence and sensitivity through the above mechanisms (↓: decreased expression).
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