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Blood pressure influences end-stage renal disease of Cd151 knockout mice
Norman Sachs, … , Hans Janssen, Arnoud Sonnenberg
Norman Sachs, … , Hans Janssen, Arnoud Sonnenberg
Published December 27, 2011
Citation Information: J Clin Invest. 2012;122(1):348-358. https://doi.org/10.1172/JCI58878.
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Research Article

Blood pressure influences end-stage renal disease of Cd151 knockout mice

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Abstract

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.

Authors

Norman Sachs, Nike Claessen, Jan Aten, Maaike Kreft, Gwendoline J.D. Teske, Anneke Koeman, Coert J. Zuurbier, Hans Janssen, Arnoud Sonnenberg

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Figure 1

CD151 binds to α3 at the cell-matrix interaction site of human podocytes in vivo.

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CD151 binds to α3 at the cell-matrix interaction site of human podocytes...
(A) Colocalization of CD151 and integrin α3 in a glomerulus of a human kidney cryosection, shown by immuno­fluorescence. (B) Strongly positive in situ PLA of CD151 and α3 in a human glomerulus along with positive (α3/β1) and negative controls (α3 and CD151 with appropriate control IgGs). (C) Transmission electron micrograph showing immunogold-labeled CD151 enriched at the basal membrane of podocyte foot processes (FP) in contact with the GBM. Scale bars: 50 μm (A and B), 500 nm (C).

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