A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells

Idiopathic nephrotic syndrome is characterized by glomerular proteinuria in the absence of infiltrating cells or immunoglobulin deposits. Although it is suspected that T cells secrete a circulating factor that leads to proteinuria by altering the permeability of the glomerular filtration barrier, the precise etiology of this syndrome is unknown. Because an animal model that mimics human idiopathic nephrotic syndrome does not exist, we developed a humanized mouse model of the disease by injecting CD34(+) stem cells or CD34(-) peripheral blood mononuclear cells from afflicted patients into immunocompromised mice. Even though both CD34(+) and CD34(-) cells induced the engraftment of human CD45(+) leukocytes in mice, only the injection of CD34(+) stem cells induced albuminuria. Ultrastructural analysis of glomeruli from the resulting proteinuric mice revealed effacement of podocyte foot processes, similar to the pathology observed in the human disease. Therefore, our data suggest that the cells responsible for the pathogenesis of idiopathic nephrotic syndrome are more likely to be immature differentiating cells rather than mature peripheral T cells.