title: Protective role for netrin-1 during diabetic nephropathy.
abstract: Recent studies implicate neuronal guidance molecules in the orchestration of inflammatory events. For example, previous studies demonstrate a functional role for netrin-1 in attenuating acute kidney injury. Here, we hypothesized a kidney-protective role for netrin-1 during chronic kidney disease, such as occurs during diabetic nephropathy. To study the role of netrin-1 during diabetic nephropathy, we induced diabetes in mice at the age of 8 weeks by streptocotozin (STZ) treatment. Sixteen weeks after STZ treatment, we examined the kidneys. Initial studies in wild-type mice demonstrated robust induction of renal, urinary, and plasma netrin-1 protein levels during diabetic nephropathy. Subsequent genetic studies in mice with partial netrin-1 deficiency (Ntrn1(+/-) mice) revealed a more severe degree of diabetic nephropathy, including more severe loss of kidney function (albuminuria, glomerular filtration rate, histology). We subsequently performed pharmacologic studies with recombinant netrin-1 treatment given continuously via osmotic pump. Indeed, netrin-1 treatment was associated with attenuated albuminuria and improved histologic scores for diabetic nephropathy compared to controls. Consistent with previous studies implicating purinergic signaling in netrin-1-elicited tissue protection, mice deficient in the Adora2b adenosine receptor were not protected. Taken together, these studies demonstrate a functional role for endogenous netrin-1 in attenuating diabetic kidney disease.
authors: Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, 12700 E 19th Avenue, Mailstop B112, Research Complex 2, Room 7121, Aurora, CO 80045, USA.
authors: Eunyoung
authors: E
authors: Tak
authors: Douglas
authors: D
authors: Ridyard
authors: Alexander
authors: A
authors: Badulak
authors: Antasia
authors: A
authors: Giebler
authors: Uladzimir
authors: U
authors: Shabeka
authors: Tilmann
authors: T
authors: Werner
authors: Eric
authors: E
authors: Clambey
authors: Radu
authors: R
authors: Moldovan
authors: Michael A
authors: MA
authors: Zimmerman
authors: Holger K
authors: HK
authors: Eltzschig
authors: Almut
authors: A
authors: Grenz
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000075388:Netrin-1; D043704:Receptor, Adenosine A2B / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D043704:Receptor, Adenosine A2B; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1
references: Physiology (Bethesda). 2009 Oct;24:298-306
references: 19815856
references: Nat Med. 2011 Nov 07;17(11):1391-401
references: 22064429
references: FASEB J. 2009 Feb;23(2):473-82
references: 18838482
references: Nat Immunol. 2009 Feb;10(2):195-202
references: 19122655
references: Nat Immunol. 2012 Jan 08;13(2):136-43
references: 22231519
references: J Exp Med. 2004 Dec 6;200(11):1395-405
references: 15583013
references: Circ Res. 2006 Nov 10;99(10):1100-8
references: 17038639
references: Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14729-34
references: 16203981
references: Trends Cardiovasc Med. 2008 Apr;18(3):103-7
references: 18436149
references: J Immunol. 2009 Apr 1;182(7):3965-8
references: 19299692
references: Nat Med. 2012 Apr 15;18(5):774-82
references: 22504483
references: J Am Soc Nephrol. 2007 Mar;18(3):833-45
references: 17267736
references: FASEB J. 2006 Nov;20(13):2242-50
references: 17077301
references: Am J Pathol. 2012 Dec;181(6):1991-2002
references: 23041393
references: Am J Physiol Renal Physiol. 2007 Nov;293(5):F1501-11
references: 17855480
references: Blood. 2006 Sep 1;108(5):1602-10
references: 16670267
references: Gastroenterology. 2009 Feb;136(2):607-18
references: 19105964
references: FASEB J. 2008 Aug;22(8):2784-97
references: 18353866
references: Gastroenterology. 2008 Nov;135(5):1739-1750.e3
references: 18804111
references: PLoS One. 2012;7(2):e32416
references: 22389701
references: J Clin Invest. 2002 Oct;110(7):993-1002
references: 12370277
references: Am J Respir Crit Care Med. 2010 Apr 15;181(8):815-24
references: 20075388
references: Circulation. 2008 Jul 8;118(2):166-75
references: 18591435
references: J Immunol. 2011 Apr 1;186(7):4367-74
references: 21357264
references: Blood. 2004 Dec 15;104(13):3986-92
references: 15319286
references: Antioxid Redox Signal. 2011 Oct 15;15(8):2221-34
references: 21126189
references: Anesthesiology. 2009 Oct;111(4):904-15
references: 19741501
references: Annu Rev Physiol. 2012;74:153-75
references: 21942704
references: J Immunol. 2010 Sep 15;185(6):3750-8
references: 20693423
references: Blood. 2008 Jun 15;111(12):5571-80
references: 18309031
references: Blood. 2008 Feb 15;111(4):2024-35
references: 18056839
references: Crit Care. 2010;14(5):R189
references: 20969752
references: N Engl J Med. 2012 Dec 13;367(24):2322-33
references: 23234515
references: J Exp Med. 2003 Sep 1;198(5):783-96
references: 12939345
references: Adv Pharmacol. 2011;61:145-86
references: 21586359
references: PLoS Med. 2008 Jun 24;5(6):e137
references: 18578565
references: J Immunol. 2010 Apr 1;184(7):4017-24
references: 20207994
references: J Am Soc Nephrol. 2011 Jan;22(1):14-20
references: 21209250
references: N Engl J Med. 2011 Feb 17;364(7):656-65
references: 21323543
references: J Clin Invest. 2012 Feb;122(2):693-710
references: 22269324
references: Cell. 1996 Dec 13;87(6):1001-14
references: 8978605
references: PLoS One. 2011;6(5):e14812
references: 21625583
references: Blood. 2009 Jan 1;113(1):224-32
references: 18812468
references: J Immunol. 2009 Apr 15;182(8):4957-64
references: 19342675
references: Curr Opin Anaesthesiol. 2011 Aug;24(4):363-9
references: 21659868
references: Gut. 2012 May;61(5):695-705
references: 21813473
references: Circulation. 2007 Mar 27;115(12):1581-90
references: 17353435
references: Circulation. 2007 Oct 16;116(16):1784-94
references: 17909107
references: J Immunol. 2011 Jan 1;186(1):549-55
references: 21098235
references: Curr Opin Crit Care. 2012 Apr;18(2):178-85
references: 22322265