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

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.

SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation

“…However, in hypoxia environments, HIF-1α stabilizes, translocates into the nucleus, and forms a complex with Hif-1 β . This complex binds to hypoxia-response element sites, regulating the expression of target genes [ 43 , 44 ]. Heme Oxygenase-1 (HO-1) stands as a downstream target gene of HIF-1α [ 45 ].…”

Autophagy and its therapeutic potential in diabetic nephropathy

“…Autophagy can be triggered by various intracellular stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and hypoxia ( 23 – 25 ), all of which are involved in the development of DN. Increasing evidence indicates that the abnormal alteration of autophagy appears to be directly linked to the emergence of DN ( 26 , 27 ).…”

The Interplay between Immune and Metabolic Pathways in Kidney Disease

“…Several genes and pathways have been linked to immunometabolic dysregulation in AKI. One of the key pathways involved in the development of AKI is the hypoxia-inducible factor 1-alpha (HIF-1α) pathway [ 75 , 76 ]. Under hypoxic conditions, HIF-1α is stabilized and activates the transcription of genes involved in glycolysis, angiogenesis, and inflammation [ 77 ].…”