Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase regulation in chronic kidney disease

Abstract

Background The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases; while prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase Factor Inhibiting HIF inhibiting (FIH). Methods We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models, we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-CT imaging. We analyzed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies from various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach, to assess its relevance in CKD. Results In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with a reduced development of fibrosis. Conclusions The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seem promising in proteinuric kidney disease.

Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits

“…Recently, it has been reported that FIH expression is increased in inflamed renal tissue during chronic kidney disease (CKD). 54 It would therefore be of interest to test for the existence and potential regulation of the FIH-IκBβ oxomer in healthy and diseased renal tissues, as an enhanced FIH-IκBβ oxomer formation may contribute to increased inflammation. However, it is currently unclear to which extent oxomers exist in healthy or diseased tissues.…”

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

“…A recent study in adenine nephropathy using micro-electrodes did not observe a large hypoxia during the disease [ 27 ]. Finally, we observed only late and patchy hypoxia in a model of progressive proteinuric kidney disease, with only some remnant tubuli being hypoxic [ 28 ].…”

“…In diabetes, several studies have shown that there is a downregulation of the HIF pathway, potentially related to hyperglycemia [ 29 ]. In our recent study, the HIF pathway was not activated in a progressive model of proteinuric kidney disease, in urinary tract obstruction, or in a late post ischemic model of kidney disease [ 28 ]. This was also the case in a chronic adenine model [ 27 , 30 ▪▪ ].…”

“…FIH is relatively neglected in the study of HIF pathway regulation, but a study published by our group showed that it was upregulated in CKD, potentially contributing to the insufficient HIF pathway activation. FIH inhibitors were tested in CKD models in vivo and showed promising results on fibrosis deposition and a trend towards limiting GFR decrease [ 28 ].…”