Phenotypic characteristics and cyclin-dependent kinase inhibitors repression in hyperplastic epithelial pathology in idiopathic focal segmental glomerulosclerosis

Hyperplastic glomerular epithelial lesion is an important determinant of th e progression of idiopathic focal segmental glomerulosclerosis (FGS). The p roliferation and differentiation of glomerular epithelial cells and parieta l epithelial cells (PECs) are regulated differently by cyclin and cyclin-de pendent kinase inhibitors (CKIs) during nephrogenesis. To access the cellul ar mechanism underlying epithelial hyperplasia in the development of FGS, t he present study applied immunohistochemistry to 21 cases of FGS to demonst rate expression of cell-cycle molecules and phenotypic characterization in proliferative epithelial lesions in FGS. The materials included segmental s clerosis (18.1%), which was divided into monolayer epithelial lesions (64.6 %) and cellular lesions (35.4%). All of the cellular lesions expressed cyto keratin, frequently with Ki-67 (82.4%) and less frequently with cyclin A (1 7.7%), but were invariably negative for podocyte markers (PHM-5 and synapto podin) and CKIs (p27(kip1) and p57(kip2)). Podocytes in nonsclerotic tuft i n the same glomeruli with cellular lesions strongly expressed CKIs and podo cyte markers. Moreover, electron microscopy showed that some large prolifer ating cells with prominent nucleoli have a broad cell base attached to Bowm an's capsule. These cells have cilia and a junctional complex with neighbor ing hyperplastic cells, some of which directly cover the glomerular basemen t membrane. This suggests that cellular lesions are of PEC origin. Monolaye r epithelial lesions also exclusively exhibited a PEC phenotype with recipr ocal expression of podocyte markers and cytokeratin. in addition, CKIs are weakly expressed in monolayer epithelial lesions, suggesting a re-entry of cell-cycle quiescent. In conclusion, proliferation of PEG, sustained by rep ression of CKIs in nature and simultaneous activation of cyclin A, is the a ctual molecular background to the cellular lesions in FGS. Cellular lesions may result in monolayer epithelial lesions that retain the PEC phenotype a nd enter a common pathway to glomerulosclerosis.