Integrin beta1-mediated matrix assembly and signaling are critical for the normal development and function of the kidney glomerulus.
The human kidneys filter 180 l of blood every day via about 2.5 million glomeruli. The three layers of the glomerular filtration apparatus consist of fenestrated endothelium, specialized extracellular matrix known as the glomerular basement membrane (GBM) and the podocyte foot processes with their modified adherens junctions known as the slit diaphragm (SD). In this study we explored the contribution of podocyte beta1 integrin signaling for normal glomerular function. Mice with podocyte specific deletion of integrin beta1 (podocin-Cre beta1-fl/fl mice) are born normal but cannot complete postnatal renal development. They exhibit detectable proteinuria on day 1 and die within a week. The kidneys of podocin-Cre beta1-fl/fl mice exhibit normal glomerular endothelium but show severe GBM defects with multilaminations and splitting including podocyte foot process effacement. The integrin linked kinase (ILK) is a downstream mediator of integrin beta1 activity in epithelial cells. To further explore whether integrin beta1-mediated signaling facilitates proper glomerular filtration, we generated mice deficient of ILK in the podocytes (podocin-Cre ILK-fl/fl mice). These mice develop normally but exhibit postnatal proteinuria at birth and die within 15 weeks of age due to renal failure. Collectively, our studies demonstrate that podocyte beta1 integrin and ILK signaling is critical for postnatal development and function of the glomerular filtration apparatus.
Kanasaki
Keizo
K
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Kanda
Yoshiko
Y
Palmsten
Kristin
K
Tanjore
Harikrishna
H
Lee
Soo Bong
SB
Lebleu
Valerie S
VS
Gattone
Vincent H
VH
Kalluri
Raghu
R
D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001485:Basement Membrane / Q000473:pathology / Q000648:ultrastructure; D002352:Carrier Proteins / Q000652:urine; D018797:Cell Cycle Proteins; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000652:urine; D004622:Embryo, Mammalian; D004727:Endothelium / Q000378:metabolism / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000652:urine; D007678:Kidney Glomerulus / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D008164:Luminescent Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000652:urine; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000652:urine; D050199:Podocytes / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology / Q000503:physiopathology; D000072260:RNA Splicing Factors; D051437:Renal Insufficiency / Q000209:etiology / Q000503:physiopathology; D012235:Rhodamines / Q000378:metabolism; D015398:Signal Transduction; D060245:Tetraspanin 29; D013997:Time Factors; D019076:Transgenes; D001616:beta-Galactosidase / Q000378:metabolism; D000099200:Scaffold Protein ILK
D015703:Antigens, CD; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005456:Fluorescent Dyes; D007211:Indoles; D019426:Integrases; D039661:Integrin beta3; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D000072260:RNA Splicing Factors; D012235:Rhodamines; D060245:Tetraspanin 29; D001616:beta-Galactosidase; D000099200:Scaffold Protein ILK; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; C407223:NPHS2 protein; C486008:Wtap protein, mouse; C113267:nephrin; C029967:nidogen; C007293:DAPI; C045073:Cre recombinase