Renoprotective Role of Hypoxia-Inducible Factors and the Mechanism

Abstract

<b><i>Background:</i></b> The kidney requires abundant blood supply, and oxygen is transmitted by diffusion through blood vessels. Most physiological metabolism of the kidney depends on oxygen, so it is very sensitive to oxygen. An increasing pool of evidence suggests that hypoxia is involved in almost all acute and chronic kidney diseases (CKDs). Vascular damage, tubular injury, and fibrosis are the main pathologies associated during hypoxia. Hypoxia-inducible factors (HIFs) are the main mediators during hypoxia, but their functions remain controversial. This article reviewed recent studies and described its mechanisms on renoprotection. <b><i>Summary:</i></b> HIF is degraded rapidly during under normal oxygen. But under hypoxia, HIFs accumulate and many target genes are regulated by HIFs. Homeostasis during injury is maintained through these genes. Pretreatment of HIF can protect the kidney from acute hypoxia and can improve repair, but HIF’s role in CKD and in renal tumor is still controversial. Due to its mechanism in kidney disease, many drugs toward HIFs are widely researched, even some of which have been used in clinical or in clinical research. <b><i>Key Messages:</i></b> In this review, we described the known physiological mechanisms, target genes, and renal protective roles of HIFs, and we discussed several drugs that are researched due to such renal protective roles.

Hypoxia-Induced Kidney Injury in Newborn Rats

“…Erythropoiesis is an early response to hypoxic exposure that can increase blood hemoglobin levels. HIF-1α accumulated under hypoxia and stimulated the expression of target genes, such as erythropoietin (EPO) and HO-1 [ 10 ]. HO-1 is thus upregulated and involved in iron and heme metabolism, reducing ferroptosis [ 26 ].…”

“…The effects of neonatal hypoxia on body weight and the brain, heart, and lungs have been investigated [ 4 , 5 , 6 , 7 , 8 ]. The kidney is also an important organ that requires high perfusion and oxygen supply, and it is sensitive to hypoxic injury [ 9 , 10 ]. However, few studies have focused on neonatal hypoxia, which is a common clinical condition in newborns with affected kidney morphology, kidney injury, and long-term effects.…”

The role of hypoxia in chronic kidney disease: a nuanced perspective

“…Some effects towards ROS production and glycogen retaining have been described in ischemic acute kidney injury models [ 51 ], and globally antifibrotic properties in these models [ 52 ] and in cisplatin AKI models [ 53 ]. This description contrast with genetic data and reflect maybe the difference between transient and constant activations of the pathways, or of a more pro-eminent activation of HIF-2α compared to HIF-1α [ 54 ]. Despite these promising preclinical results, the results in clinical studies are so far unconclusive regarding progression of renal disease.…”

Depletion of vascular adaptive mechanisms in hypertension-induced injury of the heart and kidney

“…The role of VEGF in renal physiology and pathology has been studied in various experimental models, yet results are controversial. While it has been suggested that the inhibition of VEFG in the adult kidney is not associated with prominent changes in the glomerular fi ltration barrier, thus limiting its signifi cance (19), contrasting data have pointed to its potential renoprotective effects under pathological conditions (20). In particular, VEGF may be important in maintaining glomerular integrity in the hypertensive setting (21), however its role in hypertension-induced kidney injury has been widely overlooked.…”