Podocyte biology and glomerular disease

Figure 1.  An EM photograph of two capillaries covered by podocytes. 

 
Figure 2.  After IV fluorescent dextran, we can detect vesicles in the podocytes.

The podocyte is one of three kinds of cells that make up the glomerulus, a collection of capillaries that constitute the primary blood filtration apparatus. The podocyte has a fascinating morphology with multiple long foot processes that cover the entire outside surface of the capillary. The exact function of the podocyte is unknown but it has been implicated as a component of the filtration barrier.

Our interest in podocyte biology began with studies of CD2AP knockout mice. These mice leak protein into their urine and then die by six weeks of age. Analysis of renal expression of CD2AP revealed that CD2AP is expressed almost exclusively in the podocyte. Since CD2AP appears critical for podocyte function, studies of CD2AP deficient animals have the potential to reveal the function of the podocyte.

The phenotype of CD2AP knockout and heterozygous mice suggested to us that one function of the podocyte may be to internalize proteins that become trapped in the glomerular basement membrane (GBM), the major component of the filtration barrier. Current dogma teaches that proteins above a specific size are prevented from entering the GBM but our work suggests that some portion of large proteins can enter it. Thus, an active mechanism may be required to keep the GBM barrier from becoming clogged. We have proposed that podocyte dysfunction, which would impair the ability to clear these damaging agents from the kidney, would enhance the pathogenicity of antibodies and immune complexes. If we are correct, susceptibility to kidney damage should be strongly linked to acquired or inherited changes in podocyte specific genes.

Our preliminary data show that immunoglobulin and albumin do cross the GBM and become internalized into the podocyte. A specialized antibody receptor, the neonatal Fc receptor, appears to facilitate the efficient internalization of antibody and albumin into the podocyte. Various animal models are being generated to determine whether podocyte specific impairment of endocytosis and vesicular trafficking will be sufficient to generate glomerular pathology. We have also been interested in using expression arrays to identify podocyte specific genes.

To demonstrate a role for CD2AP in human kidney disease, we are currently sequencing the CD2AP gene as well as other podocyte genes from a cohort of about 600 patients with the disease, focal segmental glomerulosclerosis, FSGS. This is performed by the Washington University Genome Sequencing Center. Our initial findings suggest that many patients express rare, private, DNA variants and that common variants are not likely to be an important cause of FSGS.