title: Advanced glycated end-products affect HIF-transcriptional activity in renal cells.
abstract: Advanced glycated end-products (AGEs) are ligands of the receptor for AGEs and increase in diabetic disease. MAPK organizer 1 (Morg1) via its binding partner prolyl-hydroxylase domain (PHD)-3 presumably plays a role in the regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α transcriptional activation. The purpose of this study was to analyze the influence of AGEs on Morg1 expression and its correlation to PHD3 activity and HIF-transcriptional activity in various renal cell types. The addition of glycated BSA (AGE-BSA) significantly up-regulated Morg1 mRNA levels in murine mesangial cells and down-regulated it in murine proximal tubular cells and differentiated podocytes. These effects were reversible when the cells were preincubated with a receptor for α-AGE antibody. AGE-BSA treatment induced a relocalization of the Morg1 cellular distribution compared with nonglycated control-BSA. Analysis of PHD3 activity demonstrated an elevated PHD3 enzymatic activity in murine mesangial cells but an inhibition in murine proximal tubular cells and podocytes after the addition of AGE-BSA. HIF-transcriptional activity was also affected by AGE-BSA treatment. Reporter gene assays and EMSAs showed that AGEs regulate HIF- transcriptional activity under nonhypoxic conditions in a cell type-specific manner. In proximal tubular cells, AGE-BSA stimulation elevated mainly HIF-1α transcriptional activity and to a lesser extent HIF-2α. We also detected an increased expression of the HIF-1α and the HIF-2α proteins in kidneys from Morg1 heterozygous (HZ) placebo mice compared with the Morg1 wild-type (WT) placebo-treated mice, and the HIF-1α protein expression in the Morg1 HZ streptozotocin-treated mice was significantly higher than the WT streptozotocin-treated mice. Analysis of isolated mesangial cells from Morg1 HZ (±) and WT mice showed an inhibited PHD3 activity and an increased HIF-transcriptional activity in cells with only one Morg1 allele. These findings are important for a better understanding of the molecular mechanisms of diabetic nephropathy.
authors.affiliation: MD, MHBA, Klinik für Innere Medizin III, Erlanger-Allee 101, D-07740 Jena, Germany. gunter.wolf@med.uni-jena.de.
authors.forename: Tzvetanka
authors.initials: T
authors.lastname: Bondeva
authors.forename: Juliane
authors.initials: J
authors.lastname: Heinzig
authors.forename: Carola
authors.initials: C
authors.lastname: Ruhe
authors.forename: Gunter
authors.initials: G
authors.lastname: Wolf
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017127:Glycation End Products, Advanced; C485502:HIF-2 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C487128:MORG1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014157:Transcription Factors; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase
references.citation: Nephrology (Carlton). 2007 Jun;12(3):261-6
references.pmid: 17498121
references.citation: Am J Nephrol. 2009;29(6):538-50
references.pmid: 19129693
references.citation: Atherosclerosis. 2013 Jan;226(1):252-7
references.pmid: 23182189
references.citation: Eur J Clin Invest. 2010 Aug;40(8):742-55
references.pmid: 20649640
references.citation: Nat Rev Mol Cell Biol. 2005 Nov;6(11):827-37
references.pmid: 16227978
references.citation: J Biol Chem. 2001 Feb 16;276(7):5085-92
references.pmid: 11060309
references.citation: Diabetes. 1994 May;43(5):676-83
references.pmid: 8168645
references.citation: Hypertension. 2003 Jun;41(6):1308-16
references.pmid: 12743015
references.citation: N Engl J Med. 1988 May 19;318(20):1315-21
references.pmid: 3283558
references.citation: Acta Neuropathol. 2005 Sep;110(3):247-54
references.pmid: 15986224
references.citation: Diab Vasc Dis Res. 2009 Jan;6(1):7-14
references.pmid: 19156622
references.citation: Arthritis Res Ther. 2009;11(5):R136
references.pmid: 19735566
references.citation: J Clin Invest. 1997 Feb 1;99(3):457-68
references.pmid: 9022079
references.citation: Circulation. 2006 Mar 7;113(9):1226-34
references.pmid: 16505177
references.citation: JACC Cardiovasc Imaging. 2012 Jan;5(1):59-67
references.pmid: 22239894
references.citation: Diabetes. 2003 Mar;52(3):621-33
references.pmid: 12606501
references.citation: Am J Physiol Renal Physiol. 2009 Nov;297(5):F1273-87
references.pmid: 19726548
references.citation: Atherosclerosis. 2012 Apr;221(2):387-96
references.pmid: 22305260
references.citation: J Am Soc Nephrol. 2000 Sep;11(9):1656-1666
references.pmid: 10966490
references.citation: J Mol Med (Berl). 2005 Nov;83(11):876-86
references.pmid: 16133426
references.citation: J Am Soc Nephrol. 2008 May;19(5):961-72
references.pmid: 18256352
references.citation: Brain Res. 2012 Oct 30;1482:22-31
references.pmid: 22982595
references.citation: Proc Natl Acad Sci U S A. 2004 May 4;101(18):6981-6
references.pmid: 15118098
references.citation: Angiogenesis. 2008;11(1):91-9
references.pmid: 18264787
references.citation: Cell. 1999 Jun 25;97(7):889-901
references.pmid: 10399917
references.citation: Neurosci Lett. 1996 Apr 12;208(1):53-6
references.pmid: 8731173
references.citation: J Biol Chem. 2003 Aug 15;278(33):30772-80
references.pmid: 12788921
references.citation: Ann N Y Acad Sci. 2011 Dec;1243:88-102
references.pmid: 22211895
references.citation: J Biol Chem. 2007 Dec 14;282(50):36330-40
references.pmid: 17942394
references.citation: Eur J Nutr. 2009 Feb;48(1):38-44
references.pmid: 19031098
references.citation: Exp Clin Endocrinol Diabetes. 2005 May;113(5):288-91
references.pmid: 15926115
references.citation: J Clin Invest. 2003 Apr;111(7):959-72
references.pmid: 12671045
references.citation: J Biol Chem. 1992 Jul 25;267(21):14998-5004
references.pmid: 1378843
references.citation: J Clin Chem Clin Biochem. 1989 Sep;27(9):577-87
references.pmid: 2691629
references.citation: Circulation. 2003 Sep 2;108(9):1070-7
references.pmid: 12912808
references.citation: Am J Nephrol. 2012;35(5):442-55
references.pmid: 22555025
references.citation: Exp Nephrol. 1996 Sep-Oct;4(5):263-6
references.pmid: 8931980
references.citation: Am J Nephrol. 2007;27(3):308-14
references.pmid: 17495427
references.citation: Diabetes Metab Rev. 1988 Aug;4(5):437-51
references.pmid: 2850143
references.citation: Curr Diab Rep. 2003 Dec;3(6):485-90
references.pmid: 14611745
references.citation: Am J Nephrol. 2009;30(4):336-45
references.pmid: 19590177
references.citation: J Biol Chem. 2006 Mar 31;281(13):8645-55
references.pmid: 16407229
references.citation: Kidney Int. 2005 Mar;67(3):944-52
references.pmid: 15698433
references.citation: J Am Soc Nephrol. 2008 Mar;19(3):486-94
references.pmid: 18256363
references.citation: Circ Cardiovasc Imaging. 2008 Nov;1(3):212-9
references.pmid: 19808545
references.citation: Am J Pathol. 1992 Jan;140(1):95-107
references.pmid: 1731533
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Am Soc Nephrol. 1996 Feb;7(2):183-90
references.pmid: 8785386
references.citation: J Cell Biol. 1988 Oct;107(4):1359-68
references.pmid: 3170633
references.citation: J Am Soc Nephrol. 2006 Jul;17(7):1970-8
references.pmid: 16762988
references.citation: Metabolism. 2003 Feb;52(2):163-7
references.pmid: 12601626
references.citation: Front Biosci (Landmark Ed). 2009 Jan 01;14:1403-13
references.pmid: 19273137
references.citation: Am J Hypertens. 2009 Jan;22(1):74-9
references.pmid: 19023277
references.citation: Contrib Nephrol. 2001;(135):92-110
references.pmid: 11705294
references.citation: Am J Pathol. 1993 Dec;143(6):1699-712
references.pmid: 8256857
references.citation: Diabetes. 2005 Jun;54(6):1615-25
references.pmid: 15919781