Abstract
Podocytes are well‐differentiated postmitotic cells whose function is largely based on their complex cytoskeletal architecture. In diseases with proteinuria, podocytes undergo morphologic changes. Podocytes react to an injurious stimulus by a reorganization of their foot process architecture that is independent of the primary injury and the cause of the proteinuria. Collapsing glomerulopathies, including the idiopathic and secondary forms due to HIV infection, have been previously considered a part of the focal sclerosing glomerulosclerosis (FSGS) spectrum. However, in contrast to FSGS, both forms of collapsing glomerulopathy are characterized by segmental and global collapse of the glomerular basement membrane (GBM) and by characteristic ultrastructural alterations in podocytes. These alterations include loss of the actin‐based cytoskeleton, a dysregulated/dedifferentiated phenotype, cellular hypertrophy, and cell proliferation. These observations raise the following questions: 1) What mechanism causes glomerular collapse and do podocytes have a role? We recently proposed that in collapsing glomerulopathies the composition of the GBM is altered and contains more immature forms of collagen IV. These observations suggest that dedifferentiated/dysregulated podocytes may participate in remodeling the GBM composition, producing fetal collagen isoforms. 2) What is the pathomechanism underlying podocyte dysregulation? Although it is still unclear which etiologic factors are responsible for the idiopathic forms of collapsing glomerulopathy, in situ hybridization studies in a transgenic mouse model of HIV‐associated collapsing glomerulopathy and on renal biopsies of patients with HIV‐associated collapsing glomerulopathy demonstrated the presence of the HIV‐1 RNA in podocytes and tubular epithelial cells. These findings suggest a direct link between viral gene expression and the dysregulation of the podocyte phenotype. 3) Another open question is how podocytes become infected in HIV‐associated collapsing glomerulopathy. HIV‐1 typically uses CD4 and a co‐receptor such as CCR5 or CXCR4 to enter cells. So far, there is no demonstration of the expression of these receptors in podocytes. These negative findings, however, do not exclude the possibility that in the kidney another, CD4 independent, co‐receptor may be used for viral cell entry. Finally, is it important to mention that collapsing glomerulopathies have a high prevalence in black patients, suggesting a link between racial background and the virus‐related podocyte injury. Microsc. Res. Tech. 57:254–262, 2002. Published 2002 Wiley‐Liss, Inc.
