DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria.
BACKGROUND
Type IV collagen in basement membranes is a ligand for the receptor tyrosine kinase discoidin domain receptor 1 (DDR1). DDR1 is expressed in renal cells and regulates cell adhesion and proliferation ex vivo. The interaction between type IV collagen and cell surface receptors is believed important for normal renal function as well as significant in chronic renal diseases and we therefore analyzed mice with a targeted deletion of DDR1.


METHODS
Homozygous DDR1 knockout mice were compared to heterozygous and wild-type animals. The quantitative and qualitative amount of proteinuria was measured by urine-microelectrophoresis. Structural changes of the kidneys were determined by immunohistochemistry, light microscopy, and electron microscopy.


RESULTS
Compared to heterozygous littermates, adult DDR1 knockout mice showed a selective middle- to high-molecular proteinuria of up to 0.3 g/L and urinary acanthocytes. There was no evidence of uremia with no change in serum urea in the first 9 months of age. Little apparent change in renal morphology was detected using light microscopy. However, electron microscopy showed a localized, subepithelial, mushroom-like isodense thickening of the glomerular basement membrane (GBM). Within these areas, a focal loss of the podocytic slit diaphragms occurred.


CONCLUSIONS
The loss of cell-matrix communication in DDR1-deficient podocytes appears to result in excess synthesis of basement membrane proteins leading to disturbed anchorage of foot processes and disruption of the slit diaphragm. Our data suggest that the interaction between type IV collagen and DDR1 plays an important role in maintaining the structural integrity of the GBM.
Gross
Oliver
O
Medical Faculty, University of Cologne, Department of Internal Medicine I, Cologne General Hospital, Merheim Medical Center, Cologne, Germany.
Beirowski
Bogdan
B
Harvey
Scott J
SJ
McFadden
Catherine
C
Chen
Dilys
D
Tam
Stephanie
S
Thorner
Paul S
PS
Smyth
Neil
N
Addicks
Klaus
K
Bloch
Wilhelm
W
Ninomiya
Yoshifumi
Y
Sado
Yoshikazu
Y
Weber
Manfred
M
Vogel
Wolfgang F
WF
D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D002461:Cell Line, Transformed; D000070818:Discoidin Domain Receptors; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D011507:Proteinuria / Q000209:etiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency*; D011975:Receptors, Mitogen / Q000172:deficiency*
D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases