Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis

Abstract

Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.Regardless of the type of initial injury to the kidney, renal hypoxia is the common final pathway of renal fibrosis 1 , which is regarded a prime target for preventing the progression of chronic kidney disease (CKD) to end-stage renal disease.Hypoxia-inducible factor (HIF) is a key transcriptional factor in the regulation of the adaptive response to hypoxia. HIF is a heterodimeric complex that has three forms (HIF-1, HIF-2, and HIF-3), which differ in their α-subunit. If the α-subunit is not hydroxylated by prolyl hydroxylase under hypoxic conditions, it cannot be recognized by von Hippel-Lindau tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex that targets HIF-α for proteosomal degradation 2 . Then, α-subunit combines with a constitutively expressed β-subunit in the nucleus. Finally, HIF regulates the expression of salient target genes that are involved in numerous biological processes, including energy metabolism, angiogenesis, erythropoiesis, iron metabolism, cell proliferation, and apoptosis 2 . HIF activation ameliorates tissue hypoxia and eventually helps the hypoxic cells survive. Even though the effect of HIF activation in CKD has been widely evaluated, the results have been inconsistent. Reduced renal fibrosis by genetic ablation of tubular HIF-1 suggested a profibrotic role of HIF 3 , while contrary results demonstrated that an HIF stabilizer exerted a beneficial effect on renal fibrosis in an animal model of CKD 4 . Accumulating evidence suggests that HIFs exert beneficial effects in diabetic nephropathy. Activation of HIFs by cobalt chloride, a non-specific pan-HIF activator, attenuated diabetes-induced alteration in oxygen m...

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“…These apparently conflicting findings may be reconciled by a framework that proposes that the effects of hypoxia‐inducible factor stimulation depend both on the isoform and the stage of chronic kidney disease. Activation of HIF‐1α early in the disease process may have deleterious effects by promoting inflammation and fibrosis, whereas stimulation of HIF‐2α at a later stage may exert an anti‐inflammatory and antifibrotic action by promoting autophagy and reducing oxidative stress . It is therefore noteworthy that AMPK activation decreases the activity of HIF‐1α, whereas increased SIRT signalling stimulates HIF‐2α …”

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