Organ distribution of erythropoietin messenger RNA in normal and uremic rats

Tan, Chorh Chuan; Eckardt, Kai‐Uwe; Ratcliffe, Peter J.

doi:10.1038/ki.1991.181

Cited by 103 publications

(60 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Another possibility left open is that the hypoxic response of the transgene is disproportionately impaired in the diseased kidney, although as yet still oxygen-regulated, as observed in renal Epo transcription. 43,44 It is also to be noted that the disease course of the RK model is so protracted and focal in nature that, although the relative increase in the transgene mRNA is small, it apparently reflects marked overexpression.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension

Tanaka

Miyata

Inagi

et al. 2004

The American Journal of Pathology

101

View full text Add to dashboard Cite

Despite the increasing need to identify and quantify tissue oxygenation at the cellular level, relatively few methods have been available. In this study, we developed a new hypoxia-responsive reporter vector using a hypoxia-responsive element of the 5 vascular endothelial growth factor untranslated region and generated a novel hypoxia-sensing transgenic rat. We then applied this animal model to the detection of tubulointerstitial hypoxia in the diseased kidney. With this model, we were able to identify diffuse cortical hypoxia in the puromycin aminonucleosideinduced nephrotic syndrome and focal and segmental hypoxia in the remnant kidney model. Expression of the hypoxia-responsive transgene increased throughout the observation period, reaching 2.2-fold at 2 weeks in the puromycin aminonucleoside model and 2.6-fold at 4 weeks in the remnant kidney model, whereas that of vascular endothelial growth factor showed a mild decrease, reflecting distinct behaviors of the two genes. The degree of hypoxia showed a positive correlation with microscopic tubulointerstitial injury in both models. Finally, we identified the localization of proliferating cell nuclear antigen-positive, ED-1-positive, and terminal dUTP nick-end labeled-positive cells in the hypoxic cortical area in the remnant kidney model. We propose here a possible pathological tie between chronic tubulointerstitial hypoxia and progressive glomerular diseases. (Am J

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension

Tanaka

Miyata

Inagi

et al. 2004

The American Journal of Pathology

101

View full text Add to dashboard Cite

show abstract

“…7,8 Furthermore, the lack of a significant rise in serum Epo under hypoxic conditions in animals that underwent bilateral nephrectomy combined with subtotal hepatectomy suggests that other organs do not contribute to the serum EPO pool. 7,9,44 Nevertheless, the ability of other sites to synthesize EPO can lead to polycythemia in certain pathologic settings, for example, in patients with uterine myomata or cerebellar hemangioblastomas. 45,46 The role of HIF-2 in hypoxia-induced erythropoiesis extends beyond the transcriptional control of EPO.…”

Section: Discussionmentioning

confidence: 99%

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

Kapitsinou

Liu

Unger³

et al. 2010

Blood

262

244

View full text Add to dashboard Cite

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...

show abstract

“…This finding also illustrates the importance of the EPO 3' HRE for hepatic EPO expression, as has been suggested by Semenza et al (18). Whether additional HIF-2α-expressing cell types, such as cardiomyocytes, glial cells, and type II pneumocytes (27), are capable of producing EPO in an HIF-2-dependent manner remains to be investigated, as low levels of Epo mRNA have been detected in many different rat tissues including the lung, spleen, brain, and testis (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo

Rankin¹,

Biju²,

Liu³

et al. 2007

J. Clin. Invest.

506

428

View full text Add to dashboard Cite

Erythropoiesis is critically dependent on erythropoietin (EPO), a glycoprotein hormone that is regulated by hypoxia-inducible factor (HIF). Hepatocytes are the primary source of extrarenal EPO in the adult and express HIF-1 and HIF-2, whose roles in the hypoxic induction of EPO remain controversial. In order to define the role of HIF-1 and HIF-2 in the regulation of hepatic EPO expression, we have generated mice with conditional inactivation of Hif-1α and/or Hif-2α (Epas1) in hepatocytes. We have previously shown that inactivation of the von Hippel-Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradation, results in increased hepatic Epo production and polycythemia independent of Hif-1α. Here we show that conditional inactivation of Hif-2α in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia. Furthermore, we found that physiological Epo expression in infant livers required Hif-2α but not Hif-1α and that the hypoxic induction of liver Epo in anemic adults was Hif-2α dependent. Since other Hif target genes such phosphoglycerate kinase 1 (Pgk) were Hif-1α dependent, we provide genetic evidence that HIF-1 and HIF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIF-2 in the liver.

show abstract

Organ distribution of erythropoietin messenger RNA in normal and uremic rats

Cited by 103 publications

References 20 publications

Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension

Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension

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

Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo

Contact Info

Product

Resources

About