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Evans Biomedical Research Center, Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118
Nephrin is an Ig-like transmembrane
protein. It is a major component of the podocyte slit diaphragm and is
essential for maintaining normal glomerular permeability.
CD2-associated protein (CD2AP) is also necessary for normal glomerular
permeability and is a putative nephrin adapter molecule. Here, we
document that nephrin and CD2AP are linked to the actin cytoskeleton.
As detected by Western blot analysis, nephrin and CD2AP were both
insoluble when cell membranes from normal rat glomeruli were extracted
with 0.5% Triton X-100 (TX-100) at 4°C in the presence of divalent
cations, but they were solubilized when the extraction included
potassium iodide (KI) to depolymerize F-actin. In addition, a small
fraction of the solubilized nephrin and CD2AP was recovered in the
low-density fractions of OptiPrep flotation gradients, which indicates
that a portion of nephrin, possibly associated with CD2AP, resides in a
cholesterol- or sphingolipid-rich region of the plasma membrane. Immunofluorescent staining of unfixed sections of normal rat kidney for
nephrin, CD2AP, and F-actin was unaltered by treatment with TX-100 but
was greatly diminished by addition of KI. Nephrin staining was slightly
reduced by cholesterol depletion with methyl-
-cyclodextrin in the
presence of TX-100 but was nearly absent after addition of KI. These
results document that nephrin anchors the slit diaphragm to the actin
cytoskeleton, possibly by linkage to CD2AP, and that nephrin traverses
a relatively cholesterol-poor region of the podocyte plasma membrane.
In addition, a small pool of actin-associated nephrin and CD2AP resides
in lipid rafts, possibly in the cholesterol-rich apical region of the
podocyte-foot processes.
glomerulus; kidney; CD2-associated protein; proteinuria; membrane lipids; lipid rafts; detergent-resistant membranes
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