Integrity of the prolyl hydroxylase domain protein 2:erythropoietin pathway in aging mice.
The central transcriptional response to hypoxia is mediated by the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. In this pathway, PHD prolyl hydroxylates and thereby negatively regulates the alpha-subunit of the transcription factor HIF (HIF-alpha). An important HIF target gene is that for erythropoietin (EPO), which controls red cell mass. Recent studies have identified PHD2 as the critical PHD isoform regulating the EPO gene. Other studies have shown that the inducibility of the HIF pathway diminishes as a function of age. Thus, an important question is whether the PHD2:EPO pathway is altered in the aging. Here, we employed a mouse line with a globally-inducible Phd2 conditional knockout allele to examine the integrity of the Phd2:Epo axis in young (six to eight months old) and aging (sixteen to twenty months old) mice. We find that acute global deletion of Phd2 results in a robust erythrocytosis in both young and aging mice, with both age groups showing marked extramedullary hematopoiesis in the spleen. Epo mRNA is dramatically upregulated in the kidney, but not in the liver, in both age groups. Conversely, other Hif targets, including Vegf, Pgk1, and Phd3 are upregulated in the liver but not in the kidney in both age groups. These findings have implications for targeting this pathway in the aging.
Li
Xiping
X
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Sutherland
Scott
S
Takeda
Kotaro
K
Fong
Guo-Hua
GH
Lee
Frank S
FS
D000375:Aging; D000818:Animals; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction
D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D004921:Erythropoietin; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
Respir Physiol Neurobiol. 2005 May 12;147(1):31-8
15848121
Am J Physiol Regul Integr Comp Physiol. 2009 Jul;297(1):R158-65
19420289
Blood. 2004 Oct 15;104(8):2263-8
15238427
J Gerontol A Biol Sci Med Sci. 2007 Jan;62(1):41-9
17301036
Blood. 2007 Feb 1;109(3):868-73
17032916
Circ Res. 2007 Dec 7;101(12):1310-8
17932327
Eur J Haematol. 2007 Mar;78(3):183-205
17253966
Blood. 2007 Sep 15;110(6):2193-6
17579185
Semin Hematol. 2008 Oct;45(4):267-75
18809098
Biogerontology. 2005;6(3):165-71
16041620
Blood Cells Mol Dis. 2008 Mar-Apr;40(2):160-5
17933562
Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R977-88
15142852
Biochemistry. 2008 Oct 28;47(43):11165-7
18834144
Nat Rev Cancer. 2008 Dec;8(12):967-75
18987634
Blood Rev. 2006 Jul;20(4):213-26
16472893
Nucleic Acids Res. 2003 Feb 15;31(4):e12
12582257
Cell Metab. 2005 Jun;1(6):393-9
16054088
J Clin Invest. 2007 Jul;117(7):1926-32
17557118
Annu Rev Pathol. 2009;4:489-515
19400694
Cell Metab. 2005 Jun;1(6):409-14
16054090
Mol Cell. 2008 May 23;30(4):393-402
18498744
Blood. 2008 Mar 15;111(6):3229-35
18056838
J Lab Clin Med. 1995 Jul;126(1):57-64
7602235
Nat Rev Mol Cell Biol. 2004 May;5(5):343-54
15122348
FEBS Lett. 1999 Dec 3;462(3):341-4
10622722
N Engl J Med. 2008 Dec 18;359(25):2685-92
19092153
Annu Rev Biochem. 2005;74:115-28
15952883
Circulation. 2007 Dec 11;116(24):2818-29
18040029
J Clin Invest. 2007 Apr;117(4):1068-77
17404621
Blood Rev. 2008 Nov;22(6):321-32
18538455
Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9
16407130
Biogerontology. 2008 Jun;9(3):169-76
18236168
Blood. 2003 Sep 1;102(5):1634-40
12750163
Cell Metab. 2005 Jun;1(6):401-8
16054089
J Biol Chem. 2000 Sep 22;275(38):29643-7
10882714
Mol Cell Biol. 2006 Nov;26(22):8336-46
16966370
Curr Top Dev Biol. 2008;82:141-67
18282520
Haematologica. 2008 Jul;93(7):963-7
18591620
Crit Rev Oncol Hematol. 2007 Nov;64(2):139-58
17656101
Annu Rev Pathol. 2007;2:145-73
18039096
Blood. 2008 Aug 15;112(4):1482-92
18451309
Blood. 2008 Mar 15;111(6):3236-44
18096761
Science. 2007 Oct 5;318(5847):62-4
17916722