Elsevier

Medical Hypotheses

Volume 82, Issue 5, May 2014, Pages 547-550
Medical Hypotheses

Prolyl hydroxylase domain-2 (PHD2) inhibition may be a better therapeutic strategy in renal anemia

https://doi.org/10.1016/j.mehy.2014.02.008Get rights and content

Abstract

Recombinant human erythropoietin (rHuEPO) has revolutionized the life of dialysis patients with anemia of chronic kidney disease (CKD). Newer erythropoietin analogues with improved profile have been introduced recently. However, there are many concerns such as safety, economy and patient compliance with these newer rHuEPo analogues. Small molecules aimed to inhibit prolyl hydroxylase domain-2 (PHD2) may prevent degradation of hypoxia inducible factor-2 (HIF2) which leads to endogenous erythropoietin production. This therapeutic intervention may not only overcome the patient compliance and economic burden but also possibly overcome the safety issues related to rHuEPO and its analogues. Moreover, PHD2 inhibitors may increase the endogenous circulating iron availability via suppression of hepcidin, a master regulator of iron homeostasis which further reduces the need for exogenous intravenous iron administration for effective erythropoiesis in renal anemia patients. In conclusion, small molecule PHD2 inhibitors may have better therapeutic efficacy and potential to address clinical concerns associated with rHuEPO and rHuEPO mimetic peptides.

Introduction

The erythropoietin (EPO) is a glycoprotein hormone produced by the peritubular cortical fibroblasts of kidney in adults. EPO is the primary stimulator and regulator of the growth and survival of erythroid progenitors, which eventually matures into the red blood cells (RBCs). Increased demand of oxygen in the body is initially satisfied by uptake and transport of oxygen through maximizing cardiac output and subsequently by optimizing oxygen carriage through acceleration of erythropoiesis [1]. The plasma EPO concentration in chronic kidney disease (CKD) patients is not sufficient to meet the increasing demand of oxygen. This leads to decline in hemoglobin (Hb) levels and causing the development of renal anemia. The factors affecting reduced EPO in renal disease are not clearly identified [2], [3]. EPO is a part of a widespread system of hypoxia-inducible factors (HIFs) [4]. HIFs are composed of one of two oxygen-regulated subunits (HIF-1 and HIF-2) that form heterodimers with a constitutive HIF-subunit. HIF-2 is the main HIF isoform responsible for regulation of EPO [5], [6], [7]. The stability and transcriptional activity of HIF is regulated by oxygen-dependent hydroxylation of two prolyl residues that facilitates the formation of ubiquitin–ligase complex making HIF amenable for proteosomal degradation [8], [9]. Hydroxylation is mediated by prolyl-hydroxylase domain (PHD) enzymes, which require oxygen and oxoglutarate as substrates (Fig. 1). Oxoglutarate analogues can therefore function as competitive prolyl-hydroxylase domain inhibitors (PHDIs). Compounds of this class have been shown to induce HIF-target genes in preclinical in vitro and in vivo models [10], [11]. It has long been known that hypoxia and iron metabolism are linked and in recent years even more complex picture of interdependence between oxygen homeostasis and iron homeostasis has emerged, considering the PHDs as a core regulator. Catalytic activity of PHDs is both oxygen-dependent and iron-dependent, and they are better known as oxygen sensors and cellular iron sensors [12]. The current therapy of renal anemia using recombinant human erythropoietin (rHuEPO) and EPO analogues have significant problem of development of resistance due to iron deficiency and higher risk of mortality because of increased cardio vascular (CV) events associated with supra-therapeutic dose of exogenous EPO [13]. Currently, there are no ideal drug treatments for renal anemia patients (Table 1).

Section snippets

Why prolyl hydroxylase domain-2 (PHD2) inhibition?

There are three PHD isoforms reported in mammals, PHD1, PHD2 and PHD3 [14]. It has been observed that PHD2 is the critical isoform in adult vascular system [15]. Point mutation in the human PHD2 gene has been associated with the polycythemia [16]. Takeda et al. performed series of gene knockout studies in mice and reported that PHD2 has major role in maintaining blood homeostasis in adult mice, whereas PHD1 and PHD3 has modulatory role [17]. PHD2 inactivation increases HIF1 and HIF2 [18], [17].

Hypotheses

The discovery of rHuEPO in late 1980’s revolutionized the treatment of anemia in CKD patients with improved quality of life due to raised Hb levels, reduced requirement of blood transfusions, and regression of left ventricular hypertrophy [26], [27]. However, CHOIR trial demonstrated poorer outcomes when patients were treated with epoetin alpha to a higher target Hb [28]. EPO treatment could cause higher risk of mortality and cardiovascular complications. The exact mechanism(s) of these effects

Conflict of interest

None.

References (36)

  • W. Jelkmann

    Erythropoietin: structure, control of production, and function

    Physiol Rev

    (1992)
  • S. Bachmann et al.

    Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin

    J Histochem Cytochem

    (1993)
  • M. Alnaeeli et al.

    Erythropoietin in brain development and beyond

    Anat Res Int

    (2012)
  • M.S. Wiesener et al.

    Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs

    FASEB J

    (2003)
  • M. Ivan et al.

    Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor

    Proc Natl Acad Sci USA

    (2002)
  • W.M. Bernhardt et al.

    Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model

    Proc Natl Acad Sci USA

    (2009)
  • M. Safran et al.

    Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production

    Proc Natl Acad Sci USA

    (2006)
  • Z. Wang et al.

    The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment

    Nephrol Dial Transplant

    (2012)
  • Cited by (0)

    View full text