Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia

Abstract

The kidney is the main physiologic source of erythropoietin (EPO) in the adult and responds to decreases in tissue oxygenation with increased EPO production. Although studies in mice with liver-specific or global gene inactivation have shown that hypoxia-inducible factor 2 (Hif-2) plays a major role in the regulation of Epo during infancy and in the adult, respectively, the contribution of renal HIF-2 signaling to systemic EPO homeostasis and the role of extrarenal HIF-2 in erythropoiesis, in the absence of kidney EPO, have not been examined directly. Here, we used Cre-loxP recombination to ablate Hif-2␣ in the kidney, whereas Hif-2-mediated hypoxia responses in the liver and other Epo-producing tissues remained intact. We found that the hypoxic induction of renal Epo is completely Hif-2 dependent and that, in the absence of renal Hif-2, hepatic Hif-2 takes over as the main regulator of serum Epo levels. Furthermore, we provide evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis. (Blood. 2010;116(16): 3039-3048) IntroductionThe glycoprotein erythropoietin (EPO) is essential for the regulation of red blood cell mass in response to changes in tissue oxygenation. EPO stimulates erythropoiesis by promoting erythroid precursor cell viability, proliferation, and differentiation, thus enhancing the oxygen-carrying capacity of blood. Its production is tightly regulated by developmental, tissue-specific, and physiologic cues. 1,2 Lack of Epo in the embryo, where it is produced by hepatocytes, leads to death from cardiac failure and anemia at embryonic day (E)13.5. 3 During late gestation, the site of EPO production switches from the fetal liver to the kidney, where fibroblast-like peritubular interstitial cells become the main physiologic source of EPO synthesis in adults. [4][5][6] Although the liver retains the ability to produce EPO in response to hypoxic stimuli, it does not contribute to the serum EPO pool under normoxic or mild hypoxic conditions. 7-9 Therefore, an impairment of renal EPO synthesis, which is typically associated with advanced chronic kidney failure, results in the development of anemia and is treated by administering recombinant EPO. 2,10 The primary physiologic stimulus of enhanced EPO gene transcription is tissue hypoxia, which can induce a several hundredfold increase in circulating serum EPO levels. 1 Although in vitro studies, using an 18-nucleotide fragment of the oxygen-sensitive 3Ј EPO regulatory element, suggested that hypoxia inducible factor-1 (HIF-1) regulates EPO in Hep3B cells, 11-13 recent genetic evidence indicates that Hif-2 has an important role in the maintenance of normal serum EPO levels. 14-16 HIF-1 and HIF-2 belong to the PER/arylhydrocarbon-receptor nuclear translocator (ARNT)/single minded family of hypoxia-regulated transcription factors and consist of an oxygen-sensitive ␣ subunit and a constitutively expressed ␤ subunit, also known as ARNT. Bo...

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

“…Importantly, two of these studies (3,5) demonstrated both a strong association between the Tibetan HIF2A haplotype and low hemoglobin concentration (which is controlled by the HIF-2␣ target gene, EPO (37)(38)(39)(40)), thereby providing compelling evidence that the HIF2A allele is a loss of function allele. Because HIF-2␣ also plays a central role in pulmonary hypertension (41)(42)(43)(44), the loss of function HIF2A allele would be predicted to blunt the erythrocytosis and pulmonary hypertension that might otherwise result from loss of PHD2 function (Fig.…”

Nitric oxide prevents axonal degeneration by inducing HIF-1–dependent expression of erythropoietin

“…The ability of EPO to prevent axonal degeneration by a variety of toxins has been described in the literature, although the signaling mechanism has yet to be defined (19,(31)(32)(33). It should be noted that HIF-2α, which is a vertebrate paralog of HIF-1α, has been shown to play an essential role in the hepatic, renal, and CNS production of EPO that maintains erythropoiesis (34,35). On the other hand, recent studies indicate that expression of inducible NO synthase is selectively activated by HIF-1α (36).…”

Hematopoiesis and bone remodeling

“…Induction of Epo gene expression in Epo-producing cells in kidney critically depended on the activation of hypoxia-inducible transcription factors (HIFs), especially HIF-2a. 3 This article suggests interplay between erythroid development and skeletal homeostasis. Singbrant and colleagues give a reasonable explanation that bone remodeling during Epo administration is necessary for the acquisition of free bone marrow spaces for erythroid cells expand.…”

“…Low-density lipoprotein (LDL) deposited in the vessel wall can stimulate inflammation and oxidative stress, generating oxidized LDL (oxLDL). [2][3][4] OxLDL promotes pro-inflammatory responses in monocytes, starting a long process that leads to dysfunctional arteries, fatty streaks, and fibrous plaques.…”