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Articles in PresS, published online ahead of print November 13, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.00290.2001
Submitted on September 17, 2001
Accepted on November 4, 2001
1 Medicine, Boston University, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: djsalant{at}acs.bu.edu.
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 at 4°C in the presence of divalent cations but were solubilized when the extraction included KI to depolymerize F-actin. In addition, a small fraction of the solubilized nephrin and CD2AP were recovered in the low-density fractions of OptiPrepTM 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-ß-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.
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