title: Hepatocyte growth factor preferentially activates the anti-inflammatory arm of NF-κB signaling to induce A20 and protect renal proximal tubular epithelial cells from inflammation.
abstract: Inflammation induces the NF-κB dependent protein A20 in human renal proximal tubular epithelial cells (RPTEC), which secondarily contains inflammation by shutting down NF-κB activation. We surmised that inducing A20 without engaging the pro-inflammatory arm of NF-κB could improve outcomes in kidney disease. We showed that hepatocyte growth factor (HGF) increases A20 mRNA and protein levels in RPTEC without causing inflammation. Upregulation of A20 by HGF was NF-κB/RelA dependent as it was abolished by overexpressing IκBα or silencing p65/RelA. Unlike TNFα, HGF caused minimal IκBα and p65/RelA phosphorylation, with moderate IκBα degradation. Upstream, HGF led to robust and sustained AKT activation, which was required for p65 phosphorylation and A20 upregulation. While HGF treatment of RPTEC significantly increased A20 mRNA, it failed to induce NF-κB dependent, pro-inflammatory MCP-1, VCAM-1, and ICAM-1 mRNA. This indicates that HGF preferentially upregulates protective (A20) over pro-inflammatory NF-κB dependent genes. Upregulation of A20 supported the anti-inflammatory effects of HGF in RPTEC. HGF pretreatment significantly attenuated TNFα-mediated increase of ICAM-1, a finding partially reversed by silencing A20. In conclusion, this is the first demonstration that HGF activates an AKT-p65/RelA pathway to preferentially induce A20 but not inflammatory molecules. This could be highly desirable in acute and chronic renal injury where A20-based anti-inflammatory therapies are beneficial.
authors: The Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Cleide G
authors: CG
authors: da Silva
authors: Elizabeth R
authors: ER
authors: Maccariello
authors: Szuhuei Wu
authors: SW
authors: Wilson
authors: Prabhakar
authors: P
authors: Putheti
authors: Soizic
authors: S
authors: Daniel
authors: Scott M
authors: SM
authors: Damrauer
authors: Clayton R
authors: CR
authors: Peterson
authors: Jeffrey J
authors: JJ
authors: Siracuse
authors: Elzbieta
authors: E
authors: Kaczmarek
authors: Christiane
authors: C
authors: Ferran
references: J Am Soc Nephrol. 2004 Nov;15(11):2868-81
references: 15504940
references: J Biol Chem. 1998 Jul 24;273(30):18793-801
references: 9668053
references: Kidney Int. 2004 Aug;66(2):523-7
references: 15253702
references: Kidney Int. 2001 Jun;59(6):2023-38
references: 11380804
references: Curr Opin Investig Drugs. 2008 Nov;9(11):1163-70
references: 18951295
references: Am J Physiol Renal Physiol. 2004 Jan;286(1):F134-43
references: 14519594
references: Int J Clin Exp Pathol. 2008 Jan 01;1(3):242-53
references: 18784816
references: Int J Mol Med. 2003 Oct;12(4):587-92
references: 12964039
references: Circulation. 2003 Sep 2;108(9):1113-8
references: 12885753
references: Hum Gene Ther. 2002 Jan 1;13(1):3-13
references: 11779411
references: J Am Soc Nephrol. 2000 Jan;11(1):152-176
references: 10616852
references: FASEB J. 2006 Jul;20(9):1418-30
references: 16816117
references: Biochem Pharmacol. 2000 Oct 15;60(8):1143-51
references: 11007952
references: Ann N Y Acad Sci. 2006 Dec;1090:188-202
references: 17384262
references: Am J Physiol Renal Physiol. 2006 Jul;291(1):F67-78
references: 16478975
references: Nature. 1970 Aug 15;227(5259):680-5
references: 5432063
references: Circ Res. 2005 Feb 18;96(3):300-7
references: 15637298
references: Blood. 2004 Oct 15;104(8):2376-84
references: 15251990
references: Blood. 1998 Apr 1;91(7):2249-58
references: 9516122
references: Immunology. 1987 Sep;62(1):153-5
references: 3653925
references: Oncogene. 2001 Dec 6;20(56):8142-7
references: 11781828
references: Hepatology. 2000 Oct;32(4 Pt 1):796-802
references: 11003625
references: Cell. 1995 Feb 24;80(4):573-82
references: 7867065
references: J Biol Chem. 2008 Mar 21;283(12):7401-10
references: 18201972
references: Kidney Int. 2004 Mar;65(3):834-45
references: 14871403
references: Biochem Biophys Res Commun. 1995 Oct 13;215(2):483-8
references: 7487981
references: Oncogene. 2005 Mar 3;24(10):1749-66
references: 15688034
references: J Exp Med. 1996 Mar 1;183(3):1013-22
references: 8642242
references: J Biochem. 1996 Apr;119(4):591-600
references: 8743556
references: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4357-61
references: 8183913
references: Kidney Int. 2001 Apr;59(4):1304-14
references: 11260391
references: Kidney Int. 1997 Jan;51(1):2-15
references: 8995712
references: J Am Soc Nephrol. 2006 Sep;17(9):2464-73
references: 16885407
references: Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):415-9
references: 1824873
references: FASEB J. 1995 Jul;9(10):899-909
references: 7542214
references: J Mol Med (Berl). 2008 Dec;86(12):1329-39
references: 18813897
references: Adv Chronic Kidney Dis. 2005 Oct;12(4):353-65
references: 16198274
references: Am J Physiol. 1988 Oct;255(4 Pt 2):F728-35
references: 2845813
references: J Exp Med. 1999 Oct 18;190(8):1135-46
references: 10523611
references: Am J Physiol. 1999 Oct;277(4):F624-33
references: 10516287
references: Hepatology. 2002 Mar;35(3):535-43
references: 11870365
references: J Biol Chem. 1992 Sep 5;267(25):17971-6
references: 1381359
references: J Biol Chem. 1993 Mar 5;268(7):5032-9
references: 8444879
references: J Biol Chem. 1992 Dec 5;267(34):24157-60
references: 1332946
references: J Biol Chem. 1990 Sep 5;265(25):14705-8
references: 2118515
references: Int J Biochem Cell Biol. 2010 Apr;42(4):519-23
references: 20026420
references: Kidney Int. 2006 Apr;69(7):1166-74
references: 16501492
references: Oncogene. 2006 Oct 30;25(51):6685-705
references: 17072322
references: Dig Dis Sci. 2005 May;50(5):914-21
references: 15906768
references: Immunol Today. 1997 Oct;18(10):483-6
references: 9357140
references: Nature. 1999 Sep 2;401(6748):86-90
references: 10485711
references: Kidney Int. 2004 Aug;66(2):480-5
references: 15253693
references: Science. 2000 Sep 29;289(5488):2350-4
references: 11009421
references: Kidney Int. 2004 Dec;66(6):2264-78
references: 15569315
references: Exp Nephrol. 1999 Sep-Dec;7(5-6):429-37
references: 10559641
references: Gene Ther. 2010 Sep;17(9):1152-61
references: 20393508
references: Nature. 1999 Sep 2;401(6748):82-5
references: 10485710
references: J Biol Chem. 2006 Jun 16;281(24):16473-81
references: 16613850
references: Kidney Int. 2005 Oct;68(4):1520-32
references: 16164629
references: Mediators Inflamm. 2009;2009:137072
references: 20182538
references: Am J Physiol Renal Physiol. 2010 Mar;298(3):F796-806
references: 20032117
references: Biochem Biophys Res Commun. 2005 Apr 29;330(1):27-33
references: 15781227
references: N Engl J Med. 1998 Nov 12;339(20):1448-56
references: 9811921
references: Cold Spring Harb Perspect Biol. 2009 Dec;1(6):a001651
references: 20457564
references: Transplantation. 2009 May 15;87(9):1283-9
references: 19424026
references: Hypertension. 2001 Feb;37(2 Pt 2):581-6
references: 11230338
references: Am J Physiol. 1994 Jan;266(1 Pt 2):F129-34
references: 8304478
references: Sci STKE. 2006 Oct 17;2006(357):re13
references: 17047224
references: Am J Transplant. 2003 Jan;3(1):3-10
references: 12492703
references: Mol Cell Biol. 2002 Feb;22(4):1060-72
references: 11809798
references: Mol Cell Biol. 1999 Jul;19(7):4798-805
references: 10373529
references: Nat Rev Drug Discov. 2008 Jun;7(6):504-16
references: 18511928
references: Nat Rev Immunol. 2009 Nov;9(11):778-88
references: 19855404
references: Biochem Pharmacol. 2006 Oct 30;72(9):1161-79
references: 16970925
references: J Biol Chem. 1992 Jun 25;267(18):12424-7
references: 1618749
references: Curr Opin Nephrol Hypertens. 2002 Jan;11(1):23-30
references: 11753083
references: J Cell Physiol. 2010 Nov;225(3):757-66
references: 20568106
references: Am J Pathol. 2008 Jul;173(1):30-41
references: 18502824
references: J Biol Chem. 1996 Jul 26;271(30):18068-73
references: 8663499
references: EMBO J. 1986 Dec 1;5(12):3133-42
references: 3102226
references: Am J Respir Cell Mol Biol. 2005 Apr;32(4):268-80
references: 15626778
references: Kidney Int. 2003 Jan;63(1):306-14
references: 12472797