Actin-depolymerizing factor cofilin-1 is necessary in maintaining mature podocyte architecture.
Actin dynamics determines podocyte morphology during development and in response to podocyte injury and might be necessary for maintaining normal podocyte morphology. Because podocyte intercellular junction receptor Nephrin plays a role in regulating actin dynamics, and given the described role of cofilin in actin filament polymerization and severing, we hypothesized that cofilin-1 activity is regulated by Nephrin and is necessary in normal podocyte actin dynamics. Nephrin activation induced cofilin dephosphorylation via intermediaries that include phosphatidylinositol 3-kinase, SSH1, 14-3-3, and LIMK in a cell culture model. This Nephrin-induced cofilin activation required a direct interaction between Nephrin and the p85 subunit of phosphatidylinositol 3-kinase. In a similar fashion, cofilin-1 dephosphorylation was observed in a rat model of podocyte injury at a time when foot process spreading is initially observed. To investigate the necessity of cofilin-1 in the glomerulus, podocyte-specific Cfl1 null mice were generated. Cfl1 null podocytes developed normally. However, these mice developed persistent proteinuria by 3 months of age, although they did not exhibit foot process spreading until 8 months, when the rate of urinary protein excretion became more exaggerated. In a mouse model of podocyte injury, protamine sulfate perfusion of the Cfl1 mutant mouse induced a broadened and flattened foot process morphology that was distinct from that observed following perfusion of control kidneys, and mutant podocytes did not recover normal structure following additional perfusion with heparin sulfate. We conclude that cofilin-1 is necessary for maintenance of normal podocyte architecture and for actin structural changes that occur during induction and recovery from podocyte injury.
Garg
Puneet
P
Division of Nephrology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Verma
Rakesh
R
Cook
Leslie
L
Soofi
Abdul
A
Venkatareddy
Madhusudan
M
George
Britta
B
Mizuno
Kensaku
K
Gurniak
Christine
C
Witke
Walter
W
Holzman
Lawrence B
LB
D000199:Actins / Q000378:metabolism; D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D051338:Cofilin 1 / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D011479:Protamines; D011485:Protein Binding; D011554:Pseudopodia / Q000378:metabolism / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000199:Actins; D051338:Cofilin 1; D008565:Membrane Proteins; D011479:Protamines; D034741:RNA, Small Interfering; C113267:nephrin; D019869:Phosphatidylinositol 3-Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human
Genes Cells. 1996 Jan;1(1):73-86
9078368
EMBO J. 2005 Feb 9;24(3):473-86
15660133
Kidney Int. 2004 Jul;66(1):91-101
15200416
Mol Biol Cell. 2001 Apr;12(4):1131-45
11294912
Curr Biol. 2004 Jan 6;14(1):11-22
14711409
J Cell Biol. 1997 Mar 24;136(6):1323-32
9087446
J Clin Invest. 2006 May;116(5):1346-59
16543952
Nature. 2006 Apr 6;440(7085):818-23
16525419
J Clin Invest. 2000 Nov;106(10):1281-90
11086029
Genes Dev. 2007 Sep 15;21(18):2347-57
17875668
Kidney Int. 2003 Aug;64(2):404-13
12846735
Nat Genet. 2010 Jan;42(1):72-6
20023659
Nephron Exp Nephrol. 2007;106(2):e67-72
17570942
J Am Soc Nephrol. 2005 Oct;16(10):2941-52
16107576
Nat Cell Biol. 2009 May;11(5):545-56
19329994
J Biol Chem. 2004 Feb 20;279(8):7193-8
14645219
Nat Cell Biol. 2006 May;8(5):485-91
16622418
J Am Soc Nephrol. 2002 Mar;13(3):630-638
11856766
Science. 2005 Jun 17;308(5729):1801-4
15879175
Kidney Int. 1999 Oct;56(4):1481-91
10504499
J Biol Chem. 2009 Mar 27;284(13):8951-62
19179337
Nat Genet. 2000 Mar;24(3):251-6
10700177
Trends Cell Biol. 1999 Sep;9(9):364-70
10461190
Curr Biol. 2002 Jan 8;12(1):79-84
11790308
Mol Cell Biol. 2008 Mar;28(6):2035-46
18212058
Oncogene. 1994 Jun;9(6):1605-12
8183554
Curr Opin Cell Biol. 2006 Feb;18(1):26-31
16337782
Cell. 2002 Jan 25;108(2):233-46
11832213
J Cell Biol. 2000 Nov 27;151(5):1119-28
11086013
Anat Rec. 1979 Oct;195(2):257-64
389091
Genesis. 2003 Jan;35(1):39-42
12481297
Dev Biol. 2005 Feb 1;278(1):231-41
15649475
Annu Rev Cell Dev Biol. 1999;15:185-230
10611961
Kidney Int. 2007 Jun;71(12):1205-14
17410103
Trends Cell Biol. 2001 Jul;11(7):288-93
11413039
EMBO J. 1999 Dec 1;18(23):6752-61
10581248
Cell. 1996 Jun 28;85(7):1047-55
8674111
J Am Soc Nephrol. 2002 Jun;13(6):1561-7
12039985
Semin Nephrol. 2003 Mar;23(2):141-6
12704574
Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9814-9
15994232
J Cell Sci. 2004 Jul 15;117(Pt 16):3499-510
15252126
Mol Cell. 1998 Mar;1(4):575-82
9660941
Science. 2003 May 23;300(5623):1298-300
12764198
Cell. 1998 Sep 4;94(5):625-34
9741627
Kidney Int. 2008 Mar;73(5):556-66
18033240
J Cell Biol. 2004 May 24;165(4):465-71
15159416
Mol Cell Biol. 2007 Dec;27(24):8698-712
17923684
J Am Soc Nephrol. 2004 Sep;15(9):2246-8
15339973
J Appl Physiol. 1962 Mar;17:343-8
14005589
Science. 2004 Apr 30;304(5671):743-6
15118165
J Clin Invest. 2004 May;113(10):1390-7
15146236
Kidney Int. 2008 Apr;73(8):903-5
18379524
J Biol Chem. 2003 Jun 6;278(23):20716-23
12668668