Pleotropic effects of hypoxia-inducible factor-prolyl hydroxylase domain inhibitors: are they clinically relevant?

Abstract

Anemia is common in patients with chronic kidney disease (CKD) and is mainly caused by insufficient production of erythropoietin from fibrotic kidney. Because anemia impairs quality of life and overall prognosis, recombinant human erythropoietin-related products (erythropoiesis-stimulating agents, ESAs) have been developed to increase hemoglobin level for decades. However, many safety concerns have been announced regarding the use of ESAs, including an increased occurrence of cardiovascular events, vascular access thrombosis, cancer progression, and recurrence. Hypoxia-inducible factor (HIF) is crucial to erythropoietin production, as a result, prolyl hydroxylase domain (PHD) enzyme inhibitors have been new therapeutic agents for the treatment of anemia in CKD. They can be administered orally, which is a preferred route for patients not undergoing hemodialysis. In clinical trials, PHD inhibitor could induce noninferior effect on erythropoiesis and improve functional iron deficiency compared with ESAs. Although no serious adverse events were reported, safety is still a concern because HIF stabilization induced by PHD inhibitor has pleotropic effects, such as angiogenesis, metabolic change, and cell survival, which might lead to unwanted deleterious effects, including fibrosis, inflammation, cardiovascular risk, and tumor growth. More molecular mechanisms of PHD inhibition and long-term clinical trials are needed to observe these pleotropic effects for the confirmation of safety and efficacy of PHD inhibitors.

Recent Update on Acute Kidney Injury-to-Chronic Kidney Disease Transition

“…It is generally considered an essential process for adaptive responses to hypoxia. 76 Recently, Li, et al 77 revealed that under hypoxia, HIF-1a can bind to Forkhead box O3 (FoxO3), a stress-responsive transcription factor known to upregulate autophagy after UUO, subsequently suppressing prolyl hydroxylation and degradation of FoxO3 by the ubiquitin-proteasome system. The removal of FoxO3 from tubular cells can lead to increased interstitial fibrosis after ischemia-reperfusion Injury, with a decrease in autophagy and more severe oxidative damage.…”

Hypoxic Inducible Factor Stabilization in Pericytes beyond Erythropoietin Production: The Good and the Bad

“…PHD inhibitors may have different effects on PHD isoforms, which may cause variations in HIF levels and, thus, pleiotropic effects. Further research is needed to elucidate how they can be used in human diseases [117]. Nowadays, there are numerous advancements and potential applications regarding the possibility of modulating HIFs to exert positive effects.…”

Umbilical cord mesenchymal stem cell; a potential therapy on reducing intimal hyperplasia in rabbit arteriovenous fistula (AVF) model, analysis the expression of HIF-1a, eNOS, and MMP-2

“…This could allow for early intervention and the implementation of preventative measures to minimize the occurrence and severity of intimal hyperplasia. 14 The mechanism through which umbilical cord mesenchymal stem cells exert their anti-intimal hyperplasia effects is multi-faceted. Firstly, these stem cells have the ability to differentiate into various cell types involved in vascular remodeling and repair.…”