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

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, integrinlinked 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.

The podocyte's response to stress: the enigma of foot process effacement

“…Deletion of any of the integrin components from podocytes has fatal consequences, most severe after deletion of ␣3-or of ␤1-integrin. Recently, it has been shown that deletion of Cd151, a member of the tetraspanin family, weakens the interaction of ␣3␤1 with laminin in the GBM and leads to a progressive glomerulopathy (5,75). Deletion of dystroglycans specifically from podocytes produces no obvious abnormalities (34).…”

Cell Receptor–Basement Membrane Interactions in Health and Disease

“…Integrin α3β1 is highly expressed by podocytes and facilitates tight binding to the GBM in order to maintain a functional filtration barrier (Sachs et al, 2012; Sachs et al, 2006). Global deletion of the integrin α3 subunit in mice results in abnormalities in glomerular development and alterations in the GBM and integrin α3-null mice die soon after birth (Kreidberg et al, 1996).…”

“…A possible mechanism whereby integrin α3β1 controls podocyte stability is via its interaction with the tetraspanin protein CD151 (Sachs et al, 2012), which mediates integrin α3β1-dependent adhesion. Interestingly, CD151-null mice show severe alterations of the GBM consisting of massive thickening and splitting and consequent kidney failure (Baleato et al, 2008; Sachs et al, 2006), thus mimicking the phenotype of mice lacking the integrin α3 subunit in podocytes (Sachs et al, 2006).…”

Protein conformation as a regulator of cell–matrix adhesion

“…In fact deletion of tetraspanin CD151, which normally associates with a3b1 integrin in adhering podocytes, leads to reduced cell adhesion and pathological integrin clustering, suggesting that other multi-transmembrane proteins modulate integrin behavior and potentially also integrin traffic in cells. 65 In the absence of such transmembrane modulators, integrin clustering could also be the consequence of a ligandmediated integrin-capturing process caused by glycocalyxmediated repulsion of the plasma membrane. 66 Alternatively, integrin clustering could also be caused by phase separations in cholesterol containing membranes and specific lipid compositions, 67 as integrin adapters such as talin and kindlin associate with PIP2 and PIP3 lipids, respectively.…”