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Published on: October 26, 2020
Blood pressure influences end-stage renal disease of Cd151 knockout mice
Norman Sachs1, Nike Claessen, Jan Aten
1Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Insights
CD151 is essential for podocyte adhesion to the kidney's glomerular basement membrane. Its absence causes kidney disease, especially under high blood pressure, highlighting CD151's role in renal health.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Medicine
Background:
- Podocytes are crucial for kidney filtration, relying on adhesion to the glomerular basement membrane (GBM).
- Integrin-α3β1, laminin, and actin are key components of the podocyte-GBM binding axis.
- Previous studies highlighted the roles of integrin-linked kinase, laminin-521, and α-actinin 4 in podocyte adhesion.
Purpose of the Study:
- To investigate the role of tetraspanin CD151 in podocyte adhesion to the GBM.
- To determine the impact of CD151 deletion on kidney function and nephropathy.
- To explore the influence of blood pressure on CD151-related kidney disease.
Main Methods:
- In situ interaction analysis of integrin α3β1 and CD151 in human podocytes.
- CRISPR-Cas9 mediated deletion of Cd151 in mouse glomerular epithelial cells.
- In vivo studies involving podocyte-specific Cd151 deletion and global Cd151-null mice under varying pressures.
- Pharmacological intervention with angiotensin-converting enzyme blockers.
Main Results:
- Integrin α3β1 interacts with CD151 in human podocytes.
- Cd151 deletion in mouse podocytes reduced adhesion to laminin by altering α3β1 distribution.
- Podocyte-specific Cd151 deletion induced glomerular nephropathy in mice.
- Elevated blood pressure exacerbated nephropathy in global Cd151-null mice.
- ACE inhibition prolonged survival in susceptible Cd151-null mice.
Conclusions:
- CD151 is a critical regulator of integrin-mediated podocyte adhesion to the GBM.
- CD151 deficiency leads to nephropathy, particularly when combined with increased blood pressure.
- Blood pressure is a significant factor in the pathogenesis of Cd151 knockout-induced nephropathy.
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.
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