The Dysregulated Podocyte Phenotype

TLDR

Podocytes are highly differentiated, postmitotic cells whose maturation involves progressive expression of markers such as WT‑1, CALLA, C3b receptor, GLEPP‑1, podocalyxin, and synaptopodin, and in collapsing forms of focal segmental glomerulosclerosis these cells undergo irreversible ultrastructural changes. The study investigates the expression of podocyte maturation markers and the proliferation marker Ki‑67 in collapsing idiopathic FSGS and HIV‑associated nephropathy relative to minimal change disease, membranous glomerulopathy, and normal adult and fetal kidneys. Immunohistochemical analysis was performed to assess the presence of mature podocyte markers and Ki‑67 in glomeruli from the disease groups and controls. In minimal change disease and membranous glomerulopathy, mature podocyte markers remained at normal levels and proliferation was absent, whereas collapsing idiopathic FSGS and HIV‑associated nephropathy exhibited loss of all markers, synaptopodin loss in 16 % of noncollapsed glomeruli, and increased Ki‑67–positive cells, indicating a dysregulated podocyte phenotype and a shared pathogenic mechanism. Abstract.

Abstract

Abstract. Podocytes are highly differentiated, postmitotic cells, whose function is largely based on their complex cytoarchitecture. The differentiation of podocytes coincides with progressive expression of maturity markers, including WT-1, CALLA, C3b receptor, GLEPP-1, podocalyxin, and synaptopodin. In collapsing forms of focal segmental glomerulosclerosis (FSGS), including idiopathic FSGS and HIV-associated nephropathy, podocytes undergo characteristic, irreversible ultrastructural changes. This study analyzes the expression pattern 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 glomerulopathy, all mature podocyte markers were retained at normal levels despite severe proteinuria and foot process fusion; no cell proliferation was observed. In contrast, in collapsing idiopathic FSGS and HIV-associated nephropathy, there was disappearance of all markers from all collapsed glomeruli and of synaptopodin from 16% of noncollapsed glomeruli. This phenotypic dysregulation of podocytes was associated with cell proliferation in both diseases. 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.