Blood pressure influences end-stage renal disease of Cd151 knockout mice.
Podocytes of the kidney adhere tightly to the underlying glomerular basement membrane (GBM) in order to maintain a functional filtration barrier. The clinical importance of podocyte binding to the GBM via an integrin-laminin-actin axis has been illustrated in models with altered function of α3β1 integrin, integrin-linked kinase, laminin-521, and α-actinin 4. Here we expanded on the podocyte-GBM binding model by showing that the main podocyte adhesion receptor, integrin α3β1, interacts with the tetraspanin CD151 in situ in humans. Deletion of Cd151 in mouse glomerular epithelial cells led to reduced adhesive strength to laminin by redistributing α3β1 at the cell-matrix interface. Moreover, in vivo podocyte-specific deletion of Cd151 led to glomerular nephropathy. Although global Cd151-null B6 mice were not susceptible to renal disease, as has been shown previously, increasing blood and transcapillary filtration pressure induced nephropathy in these mice. Importantly, blocking the angiotensin-converting enzyme in renal disease-susceptible global Cd151-null FVB mice prolonged their median life span. Together, these results establish CD151 as a crucial modifier of integrin-mediated adhesion of podocytes to the GBM and show that blood pressure is an important factor in the initiation and progression of Cd151 knockout-induced nephropathy.
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Norman
N
Sachs
Nike
N
Claessen
Jan
J
Aten
Maaike
M
Kreft
Gwendoline J D
GJ
Teske
Anneke
A
Koeman
Coert J
CJ
Zuurbier
Hans
H
Janssen
Arnoud
A
Sonnenberg
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D050533:Glomerular Basement Membrane / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D039201:Integrin alpha3beta1 / Q000502:physiology; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000473:pathology / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D060185:Tetraspanin 24 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; C554715:CD151 protein, human; C554716:Cd151 protein, mouse; D039201:Integrin alpha3beta1; D060185:Tetraspanin 24