title: Netrin-1 overexpression protects kidney from ischemia reperfusion injury by suppressing apoptosis.
abstract: Netrin-1, a diffusible laminin-related protein, is highly expressed in the kidney. However, the pathophysiological roles of netrin-1 in the kidney are unknown. To address this question directly, we used transgenic mice that overexpress chicken netrin-1 in the kidney. Netrin-1 overexpression was confirmed by real-time RT-PCR and Western blot analysis. Eight-week-old wild-type and transgenic mice were subjected to 26 minutes of renal ischemia followed by reperfusion for 72 hours. Wild-type mice developed more severe renal dysfunction by 24 hours than netrin-1 transgenic mice. Functional improvement was associated with better preservation of morphology, reduced cytokine expression, and reduced oxidative stress in the kidney of transgenic mice as compared with wild-type mice. In addition, both basal and reperfusion-induced cell proliferation were dramatically increased in transgenic kidneys as determined by Ki-67 staining. Interestingly, ischemia reperfusion induced a large increase in apoptosis in wild-type mice but not in netrin-1 transgenic mice that was associated with reduced caspase-3 activation in the transgenic kidney. These results suggest that netrin-1 protects renal tubular epithelial cells against ischemia reperfusion-induced injury by increasing proliferation and suppressing apoptosis.
authors.affiliation: Division of Nephrology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.forename: William Brian
authors.initials: WB
authors.lastname: Reeves
authors.forename: Laurent
authors.initials: L
authors.lastname: Pays
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002645:Chickens; D005786:Gene Expression Regulation; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D000075388:Netrin-1; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1
references.citation: J Am Soc Nephrol. 2006 Jun;17(6):1503-20
references.pmid: 16707563
references.citation: Development. 2008 Feb;135(4):659-67
references.pmid: 18223200
references.citation: Trends Cell Biol. 2004 Apr;14(4):153-5
references.pmid: 15134068
references.citation: Nature. 2004 Sep 2;431(7004):80-4
references.pmid: 15343335
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14465-70
references.pmid: 18796601
references.citation: J Cereb Blood Flow Metab. 2008 Sep;28(9):1543-51
references.pmid: 18461079
references.citation: Kidney Int. 2004 Aug;66(2):506-9
references.pmid: 15253698
references.citation: Nature. 2004 Nov 11;432(7014):179-86
references.pmid: 15510105
references.citation: Am J Physiol Renal Physiol. 2007 Jul;293(1):F325-32
references.pmid: 17494092
references.citation: Cancer Biol Ther. 2007 May;6(5):743-8
references.pmid: 17387275
references.citation: Am J Physiol Renal Physiol. 2008 Jun;294(6):F1473-80
references.pmid: 18434389
references.citation: Kidney Int. 2004 Aug;66(2):480-5
references.pmid: 15253693
references.citation: Am J Physiol Renal Physiol. 2009 Apr;296(4):F723-9
references.pmid: 19211685
references.citation: EMBO J. 2001 Jun 1;20(11):2715-22
references.pmid: 11387206
references.citation: Curr Biol. 2004 May 25;14(10):897-905
references.pmid: 15186747
references.citation: Transplantation. 2006 Dec 27;82(12):1728-32
references.pmid: 17198267
references.citation: Nat Cell Biol. 2003 Mar;5(3):216-23
references.pmid: 12598906
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4850-5
references.pmid: 18353983
references.citation: Am J Physiol Renal Physiol. 2003 Jul;285(1):F87-94
references.pmid: 12657560
references.citation: Nature. 1998 Oct 22;395(6704):801-4
references.pmid: 9796814
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3416-21
references.pmid: 11248093
references.citation: J Clin Invest. 2007 Oct;117(10):2847-59
references.pmid: 17853945
references.citation: J Biol Chem. 2003 May 9;278(19):17483-90
references.pmid: 12598531
references.citation: Neuroscience. 2008 Oct 15;156(3):475-82
references.pmid: 18786616
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6530-5
references.pmid: 16611730
references.citation: Biochem Biophys Res Commun. 2007 Nov 3;362(4):1057-62
references.pmid: 17825258
references.citation: Am J Physiol Renal Physiol. 2008 Apr;294(4):F739-47
references.pmid: 18216145
references.citation: Physiol Rev. 2004 Apr;84(2):411-30
references.pmid: 15044679
references.citation: Apoptosis. 2004 Jan;9(1):37-49
references.pmid: 14739597
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14729-34
references.pmid: 16203981
references.citation: EMBO J. 2005 Mar 23;24(6):1192-201
references.pmid: 15729359
references.citation: Science. 2006 Aug 4;313(5787):640-4
references.pmid: 16809490
references.citation: Am J Physiol. 1996 Dec;271(6 Pt 2):F1211-6
references.pmid: 8997395
references.citation: J Clin Invest. 1999 Sep;104(5):541-9
references.pmid: 10487768
references.citation: Nat Rev Cancer. 2004 Dec;4(12):978-87
references.pmid: 15573119