Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis.
Alterations in glomerular podocyte cell-cell and cell-matrix contacts are key events in progressive glomerular failure. Integrin-linked kinase (ILK) has been implicated in podocyte cell-matrix interaction and is induced in proteinuria. For evaluation of ILK function in vivo, mice with a Cre-mediated podocyte-specific ILK inactivation were generated. These mice seemed normal at birth but developed progressive focal segmental glomerulosclerosis and died in terminal renal failure. The first ultrastructural lesions that are seen at onset of albuminuria are glomerular basement membrane (GBM) alterations with a significant increase in true harmonic mean GBM thickness. Podocyte foot process effacement and loss of slit diaphragm followed with progression to unselective proteinuria. No significant reduction of slit membrane molecules (podocin and nephrin), key GBM components (fibronectin, laminins, and collagen IV isoforms), or podocyte integrins could be observed at onset of proteinuria. However, alpha3-integrins were relocalized into a granular pattern along the GBM, consistent with altered integrin-mediated matrix assembly in ILK-deficient podocytes. As the increased GBM thickness precedes structural podocyte lesions and key components of the GBM were expressed at comparable levels to controls, these data suggest an essential role of ILK for the close interconnection of GBM structure and podocyte function.
El-Aouni
Chiraz
C
Division of Nephrology, Department of Internal Medicine, University of Michigan, 1570 MSRB II, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0676, USA. kretzler@umich.edu
Herbach
Nadja
N
Blattner
Simone M
SM
Henger
Anna
A
Rastaldi
Maria P
MP
Jarad
George
G
Miner
Jeffrey H
JH
Moeller
Marcus J
MJ
St-Arnaud
Rene
R
Dedhar
Shoukat
S
Holzman
Lawrence B
LB
Wanke
Ruediger
R
Kretzler
Matthias
M
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D015996:Survival Rate; D000099200:Scaffold Protein ILK
D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK