title: α1β1 integrin/Rac1-dependent mesangial invasion of glomerular capillaries in Alport syndrome.
abstract: Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. L-NAME salt-induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin α1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin α1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin α2-deficient Alport mice show reduced mesangial process invasion, and cultured laminin α2-null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin α1β1-dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology.
authors.affiliation: Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska.
authors.forename: Marisa
authors.initials: M
authors.lastname: Zallocchi
authors.affiliation: Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska.
authors.forename: Brianna M
authors.initials: BM
authors.lastname: Johnson
authors.affiliation: Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meehan
authors.affiliation: Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska.
authors.forename: Duane
authors.initials: D
authors.lastname: Delimont
authors.affiliation: Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska; Department of Biochemistry, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: dominic.cosgrove@boystown.org.
authors.forename: Dominic
authors.initials: D
authors.lastname: Cosgrove
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D005920:Glomerular Mesangium / Q000098:blood supply* / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D039222:Integrin alpha1beta1 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D021381:Protein Transport / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D039222:Integrin alpha1beta1; D007797:Laminin; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
references.citation: FASEB J. 2004 Oct;18(13):1541-3
references.pmid: 15319369
references.citation: Kidney Int. 1998 Dec;54(6):1857-66
references.pmid: 9853250
references.citation: Am J Pathol. 1991 Aug;139(2):371-82
references.pmid: 1867323
references.citation: J Biol Chem. 2004 Sep 17;279(38):39989-98
references.pmid: 15262974
references.citation: Cell. 2001 Aug 24;106(4):489-98
references.pmid: 11525734
references.citation: Kidney Int. 2009 Nov;76(9):968-76
references.pmid: 19710627
references.citation: Kidney Int. 1999 Oct;56(4):1468-80
references.pmid: 10504498
references.citation: J Am Soc Nephrol. 2002 Nov;13(11):2648-56
references.pmid: 12397034
references.citation: J Clin Invest. 1997 May 15;99(10):2470-8
references.pmid: 9153291
references.citation: J Biol Chem. 2000 Apr 28;275(17):12719-24
references.pmid: 10777566
references.citation: Am J Physiol Cell Physiol. 2011 Mar;300(3):C397-405
references.pmid: 21123730
references.citation: J Am Soc Nephrol. 2001 Feb;12(2):252-260
references.pmid: 11158215
references.citation: Matrix Biol. 2010 Jun;29(5):346-56
references.pmid: 20307660
references.citation: Dev Biol. 1996 May 1;175(2):301-13
references.pmid: 8626034
references.citation: Kidney Int. 2003 Feb;63(2):438-46
references.pmid: 12631109
references.citation: Kidney Int. 2001 Sep;60(3):1037-46
references.pmid: 11532098
references.citation: Am J Pathol. 2000 Nov;157(5):1649-59
references.pmid: 11073824
references.citation: Blood. 2007 Feb 15;109(4):1524-32
references.pmid: 17023588
references.citation: J Cell Sci. 2009 Jan 15;122(Pt 2):199-206
references.pmid: 19118212
references.citation: Nat Genet. 1994 Sep;8(1):77-81
references.pmid: 7987396
references.citation: Am J Pathol. 2008 Mar;172(3):761-73
references.pmid: 18258846
references.citation: J Cell Biol. 2006 Oct 9;175(1):33-9
references.pmid: 17015618
references.citation: J Clin Invest. 2012 Jan;122(1):348-58
references.pmid: 22201679
references.citation: Genes Dev. 1996 Dec 1;10(23):2981-92
references.pmid: 8956999
references.citation: J Digit Imaging. 2010 Aug;23(4):463-74
references.pmid: 19760293
references.citation: Am J Pathol. 1988 Dec;133(3):609-14
references.pmid: 3202119
references.citation: Kidney Int. 1999 Nov;56(5):1662-73
references.pmid: 10571774
references.citation: J Cell Biol. 2010 Dec 27;191(7):1261-9
references.pmid: 21173111
references.citation: J Cell Biol. 1997 May 5;137(3):685-701
references.pmid: 9151674
references.citation: J Biol Chem. 1992 Feb 25;267(6):4137-42
references.pmid: 1740456
references.citation: Cell. 1995 Apr 7;81(1):53-62
references.pmid: 7536630
references.citation: J Cell Sci. 1995 Feb;108 ( Pt 2):537-44
references.pmid: 7768999
references.citation: Nephrol Dial Transplant. 2007 Apr;22(4):1062-9
references.pmid: 17287218
references.citation: Biochem Biophys Res Commun. 2004 Apr 30;317(2):384-9
references.pmid: 15063769
references.citation: Exp Cell Res. 2004 Dec 10;301(2):211-22
references.pmid: 15530857
references.citation: EMBO J. 1991 Sep;10(9):2375-85
references.pmid: 1714374
references.citation: Kidney Int. 2012 Mar;81(5):494-501
references.pmid: 22166847
references.citation: J Am Soc Nephrol. 2009 Jun;20(6):1179-87
references.pmid: 19470685
references.citation: Oncogene. 2005 Apr 28;24(19):3154-65
references.pmid: 15735674
references.citation: PLoS Med. 2006 Apr;3(4):e100
references.pmid: 16509766
references.citation: J Biol Chem. 1998 Apr 10;273(15):8767-75
references.pmid: 9535854
references.citation: Am J Pathol. 2008 Oct;173(4):927-37
references.pmid: 18787104
references.citation: Kidney Int. 1996 Nov;50(5):1445-63
references.pmid: 8914010
references.citation: J Biol Chem. 2001 Aug 10;276(32):30188-98
references.pmid: 11402028
references.citation: J Biol Chem. 2005 Jan 7;280(1):578-84
references.pmid: 15513924
references.citation: Science. 1990 Jun 8;248(4960):1224-7
references.pmid: 2349482
references.citation: Kidney Int. 2003 Mar;63(3):826-34
references.pmid: 12631063
references.citation: J Gen Virol. 2009 Dec;90(Pt 12):2902-2911
references.pmid: 19710257
references.citation: J Cell Biochem. 2011 Jun;112(6):1572-84
references.pmid: 21344485
references.citation: Am J Pathol. 2006 Jul;169(1):32-46
references.pmid: 16816359
references.citation: J Am Soc Nephrol. 2007 Sep;18(9):2465-72
references.pmid: 17699809
references.citation: Pediatr Nephrol. 1998 May;12(4):269-74
references.pmid: 9655355
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1939-44
references.pmid: 15677332
references.citation: Mol Biol Cell. 2002 Mar;13(3):902-14
references.pmid: 11907271