title: Increased atherosclerotic lesion formation and vascular leukocyte accumulation in renal impairment are mediated by interleukin-17A.
abstract: BACKGROUND
  Atherosclerosis is a major cause of death in patients with chronic kidney disease. Chronic inflammation of the arterial wall including invasion, proliferation, and differentiation of leukocytes is important in atherosclerotic lesion development. How atherosclerotic inflammation is altered in renal impairment is incompletely understood.
  
  
  OBJECTIVE
  This study analyzed leukocytes of the atherosclerotic aorta in mice with impaired and normal renal function and studied a mechanism for the alteration in aortic myeloid leukocytes.
  
  
  RESULTS
  Unilateral nephrectomy significantly decreased glomerular filtration rate and increased atherosclerotic lesion size and aortic leukocyte numbers in 2 murine atherosclerosis models, apolipoprotein E (Apoe(-/-)) and low-density lipoprotein (LDL) receptor-deficient (LDLr(-/-)) mice. The number of aortic myeloid cells increased significantly. They took-up less oxidized LDL, whereas CD11c expression, interaction with T cells, and aortic T cell proliferation were significantly enhanced in renal impairment. In human peripheral blood mononuclear cell cultures, chronic kidney disease serum decreased lipid uptake and increased human leukocyte antigen II (HLA II) expression. Supplementation with interleukin-17A similarly increased HLA II and CD11c expression and impaired oxidized LDL uptake. Interleukin-17A expression was increased in atherosclerotic mice with renal impairment. Ablation of interleukin-17A in LDLr(-/-) mice by lethal irradiation and reconstitution with Il17a(-/-) bone marrow abolished the effect of renal impairment on aortic CD11b(+) myeloid cell accumulation, CD11c expression, and cell proliferation. Atherosclerotic lesion size was decreased to levels observed in normal kidney function.
  
  
  CONCLUSIONS
  Kidney function modifies arterial myeloid cell accumulation and phenotype in atherosclerosis. Our results suggest a central role for interleukin-17A in aggravation of vascular inflammation and atherosclerosis in renal impairment.
authors.affiliation: From the Department of Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Shuwang
authors.initials: S
authors.lastname: Ge
authors.forename: Barbara
authors.initials: B
authors.lastname: Hertel
authors.forename: Ekaterina K
authors.initials: EK
authors.lastname: Koltsova
authors.forename: Inga
authors.initials: I
authors.lastname: Sörensen-Zender
authors.forename: Jan T
authors.initials: JT
authors.lastname: Kielstein
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Sibylle
authors.initials: S
authors.lastname: von Vietinghoff
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001025:Aortitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D039521:CD11c Antigen / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D020381:Interleukin-17 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D039521:CD11c Antigen; D000949:Histocompatibility Antigens Class II; D020381:Interleukin-17; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein
keywords: atherosclerosis; interleukin-17; leukocytes; renal insufficiency; vascular inflammation
references.citation: Clin J Am Soc Nephrol. 2008 Nov;3(6):1599-605
references.pmid: 18815240
references.citation: FASEB J. 1997 Nov;11(13):1199-207
references.pmid: 9367355
references.citation: J Am Soc Nephrol. 2006 Feb;17(2):433-41
references.pmid: 16371432
references.citation: J Int Med Res. 2009 May-Jun;37(3):862-6
references.pmid: 19589271
references.citation: J Am Soc Nephrol. 2004 Jun;15(6):1495-503
references.pmid: 15153560
references.citation: Immunity. 2011 Feb 25;34(2):149-62
references.pmid: 21349428
references.citation: Biochem Biophys Res Commun. 2009 Oct 16;388(2):261-5
references.pmid: 19660432
references.citation: J Exp Med. 2007 Oct 1;204(10):2449-60
references.pmid: 17875676
references.citation: Curr Opin Pharmacol. 2013 Apr;13(2):180-5
references.pmid: 23395156
references.citation: Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):273-80
references.pmid: 22116098
references.citation: J Am Soc Nephrol. 2009 Jun;20(6):1264-74
references.pmid: 19389852
references.citation: J Immunol. 2010 Nov 1;185(9):5619-27
references.pmid: 20935201
references.citation: JAMA. 2007 Nov 7;298(17):2038-47
references.pmid: 17986697
references.citation: Am Heart J. 2012 Mar;163(3):399-406
references.pmid: 22424010
references.citation: Hypertension. 2010 Feb;55(2):500-7
references.pmid: 20038749
references.citation: J Am Soc Nephrol. 2003 Feb;14(2):311-6
references.pmid: 12538731
references.citation: Atherosclerosis. 2011 Apr;215(2):471-4
references.pmid: 21300351
references.citation: J Am Soc Nephrol. 2006 Jul;17(7):2034-47
references.pmid: 16738019
references.citation: Kidney Int. 2011 Sep;80(6):572-86
references.pmid: 21750584
references.citation: Cytokine Growth Factor Rev. 2010 Dec;21(6):463-9
references.pmid: 21075042
references.citation: Nat Rev Immunol. 2008 Oct;8(10):802-15
references.pmid: 18825131
references.citation: J Am Soc Nephrol. 2003 Oct;14(10):2466-74
references.pmid: 14514724
references.citation: Circ Res. 2012 Mar 2;110(5):675-87
references.pmid: 22302786
references.citation: Nephrol Dial Transplant. 2005 Sep;20(9):1868-73
references.pmid: 15886215
references.citation: J Exp Med. 2009 Sep 28;206(10):2141-9
references.pmid: 19752185
references.citation: Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1565-72
references.pmid: 21474820
references.citation: Circulation. 2007 Jul 3;116(1):85-97
references.pmid: 17606856
references.citation: N Engl J Med. 2004 Sep 23;351(13):1296-305
references.pmid: 15385656
references.citation: Nat Rev Immunol. 2006 Jul;6(7):508-19
references.pmid: 16778830
references.citation: Kidney Int. 2006 Jul;70(2):371-6
references.pmid: 16738532
references.citation: J Immunol. 2009 Dec 15;183(12):8167-75
references.pmid: 20007582
references.citation: Am J Epidemiol. 2008 May 15;167(10):1226-34
references.pmid: 18385206
references.citation: J Am Coll Cardiol. 2011 May 24;57(21):2194-204
references.pmid: 21596236
references.citation: J Am Soc Nephrol. 2005 Jan;16(1):109-16
references.pmid: 15563564
references.citation: Immunol Lett. 2012 Jan 30;141(2):181-9
references.pmid: 22004873
references.citation: J Clin Invest. 2012 Sep;122(9):3114-26
references.pmid: 22886300
references.citation: Circulation. 2010 Apr 20;121(15):1746-55
references.pmid: 20368519
references.citation: J Immunol. 2010 Jul 1;185(1):670-8
references.pmid: 20519647
references.citation: J Am Soc Nephrol. 2009 Jul;20(7):1453-64
references.pmid: 19478096
references.citation: N Engl J Med. 2001 Sep 20;345(12):861-9
references.pmid: 11565518
references.citation: Circulation. 2009 May 26;119(20):2708-17
references.pmid: 19433759
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14942-7
references.pmid: 19706425
references.citation: Eur J Immunol. 2012 Mar;42(3):726-36
references.pmid: 22161142
references.citation: Immunity. 2011 Nov 23;35(5):819-31
references.pmid: 22078798
references.citation: Science. 2002 Jun 7;296(5574):1869-73
references.pmid: 12016203
references.citation: J Exp Med. 2009 Sep 28;206(10):2067-77
references.pmid: 19737863
references.citation: Arterioscler Thromb Vasc Biol. 2011 May;31(5):969-79
references.pmid: 21508343
references.citation: Circulation. 2009 May 5;119(17):2367-75
references.pmid: 19380622
references.citation: Circ Res. 2008 Oct 24;103(9):965-73
references.pmid: 18832748
references.citation: Circ Res. 2012 Oct 26;111(10):1274-85
references.pmid: 22927332
references.citation: Am J Pathol. 1995 Sep;147(3):668-77
references.pmid: 7677178
references.citation: Am J Kidney Dis. 2007 Feb;49(2 Suppl 2):S12-154
references.pmid: 17276798
references.citation: Circ Res. 2013 May 24;112(11):1456-65
references.pmid: 23572498
references.citation: J Am Soc Nephrol. 2006 Dec;17(12 Suppl 3):S169-73
references.pmid: 17130257
references.citation: Nephrol Dial Transplant. 2004 Mar;19(3):566-73
references.pmid: 14767010
references.citation: Science. 2013 Jan 11;339(6116):166-72
references.pmid: 23307734
references.citation: Eur Heart J. 2005 Sep;26(17):1700-4
references.pmid: 15855191
references.citation: Nat Rev Nephrol. 2013 May;9(5):255-65
references.pmid: 23507826
references.citation: Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1277-82
references.pmid: 19667109
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14948-53
references.pmid: 19706421