Laminin α1 regulates age-related mesangial cell proliferation and mesangial matrix accumulation through the TGF-β pathway.
Laminin α1 (LAMA1), a subunit of the laminin-111 basement membrane component, has been implicated in various biological functions in vivo and in vitro. Although LAMA1 is present in kidney, its roles in the kidney are unknown because of early embryonic lethality. Herein, we used a viable conditional knockout mouse model with a deletion of Lama1 in the epiblast lineage (Lama1(CKO)) to study the role of LAMA1 in kidney development and function. Adult Lama1(CKO) mice developed focal glomerulosclerosis and proteinuria with age. In addition, mesangial cell proliferation was increased, and the mesangial matrix, which normally contains laminin-111, was greatly expanded. In vitro, mesangial cells from Lama1(CKO) mice exhibited significantly increased proliferation compared with those from controls. This increased proliferation was inhibited by the addition of exogenous LAMA1-containing laminin-111, but not by laminin-211 or laminin-511, suggesting a specific role for LAMA1 in regulating mesangial cell behavior. Moreover, the absence of LAMA1 increased transforming growth factor (TGF)-β1-induced Smad2 phosphorylation, and inhibitors of TGF-β1 receptor I kinase blocked Smad2 phosphorylation in both control and Lama1(CKO) mesangial cells, indicating that the increased Smad2 phosphorylation occurred in the absence of LAMA1 via the TGF-β1 receptor. These findings suggest that LAMA1 plays a critical role in kidney function and kidney aging by regulating the mesangial cell population and mesangial matrix deposition through TGF-β/Smad signaling.
Research Institute for Diseases of Old Age, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Liang
L
Ning
Department of Anatomy and Life Structure, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Hidetake
H
Kurihara
Research Institute for Diseases of Old Age, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Susana
S
de Vega
Research Institute for Diseases of Old Age, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
Naoki
N
Ichikawa-Tomikawa
Research Institute for Diseases of Old Age, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Zhuo
Z
Xu
Research Institute for Diseases of Old Age, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Risa
R
Nonaka
Division of Proteomics and Biomolecular Science, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Saiko
S
Kazuno
National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
Yoshihiko
Y
Yamada
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Jeffrey H
JH
Miner
Research Institute for Diseases of Old Age, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Neurology, BioMedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address: ehirasaw@juntendo.ac.jp.
Eri
E
Arikawa-Hirasawa
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D005921:Glomerulonephritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D007797:Laminin; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C084098:laminin A