The dysregulated podocyte phenotype: A novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy

Podocytes are highly differentiated, postmitotic cells, whose function is l argely based on their complex cytoarchitecture. The differentiation of podo cytes coincides with progressive expression of maturity markers, including WT-1, CALLA, C3b receptor, GLEPP-1, podocalyxin, and synaptopodin. In colla psing forms of focal segmental glomerulosclerosis (FSGS), including idiopat hic FSGS and HIV-associated nephropathy, podocytes undergo characteristic, irreversible ultrastructural changes. This study analyzes the expression pa ttern of the above differentiation markers and of the proliferation marker Ki-67 in collapsing idiopathic FSGS and HIV-associated nephropathy compared with minimal change disease, membranous glomerulopathy, as well as normal adult and fetal human kidney. In minimal change disease and membranous glom erulopathy, all mature podocyte markers were retained at normal levels desp ite severe proteinuria and foot process fusion; no cell proliferation was o bserved. In contrast, in collapsing idiopathic FSGS and HN-associated nephr opathy, there was disappearance of all markers from all collapsed glomeruli and of synaptopodin from 16% of noncollapsed glomeruli. This phenotypic dy sregulation of podocytes was associated with cell proliferation in both dis eases. It is concluded that the loss of specific podocyte markers defines a novel dysregulated podocyte phenotype and suggests a common pathomechanism in collapsing FSGS, whether idiopathic or HIV-associated.