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Department
of Pathology, Institute of Clinical Medicine (MN) and Basic Medical Sciences
(YS, SS, TW), University of Tsukuba, Ibaraki; and Department of Pediatric
Nephrology (MH, KI), Laboratory of Pathology (SH), Tokyo Women's Medical
College, Tokyo, Japan
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SUMMARY:
Hyperplastic glomerular epithelial lesion is an important determinant
of the progression of idiopathic focal segmental glomerulosclerosis (FGS).
The proliferation and differentiation of glomerular epithelial cells and
parietal epithelial cells (PECs) are regulated differently by cyclin and
cyclin-dependent kinase inhibitors (CKIs) during nephrogenesis. To access
the cellular mechanism underlying epithelial hyperplasia in the development
of FGS, the present study applied immunohistochemistry to 21 cases of
FGS to demonstrate expression of cell-cycle molecules and phenotypic characterization
in proliferative epithelial lesions in FGS. The materials included segmental
sclerosis (18.1%), which was divided into monolayer epithelial lesions
(64.6%) and cellular lesions (35.4%). All of the cellular lesions expressed
cytokeratin, frequently with Ki-67 (82.4%) and less frequently with cyclin
A (17.7%), but were invariably negative for podocyte markers (PHM-5 and
synaptopodin) and CKIs (p27kip1 and p57kip2). Podocytes
in nonsclerotic tuft in the same glomeruli with cellular lesions strongly
expressed CKIs and podocyte markers. Moreover, electron microscopy showed
that some large proliferating cells with prominent nucleoli have a broad
cell base attached to Bowman's capsule. These cells have cilia and a junctional
complex with neighboring hyperplastic cells, some of which directly cover
the glomerular basement membrane. This suggests that cellular lesions
are of PEC origin. Monolayer epithelial lesions also exclusively exhibited
a PEC phenotype with reciprocal 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 PEC, sustained by repression of CKIs in nature and simultaneous activation
of cyclin A, is the actual molecular background to the cellular lesions
in FGS. Cellular lesions may result in monolayer epithelial lesions that
retain the PEC phenotype and enter a common pathway to glomerulosclerosis.
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