Glomerular epithelial-mesenchymal transdifferentiation in pauci-immune crescentic glomerulonephritis.
BACKGROUND
Among the cellular changes occurring in renal fibrosis, epithelial-mesenchymal cell transdifferentiation or transition (EMT) is a phenomenon characterized in epithelial cells by loss of epithelial markers and acquisition of mesenchymal phenotype and of fibrosing properties.


METHODS
To test the hypothesis that EMT is involved in human pauci-immune crescentic glomerulonephritis (PICGN), we studied 17 renal biopsies from 11 PICGN patients for: (i) proliferating cell nuclear antigen (PCNA) and cell cycle inhibitors (cyclin-dependent kinase inhibitors) p27 and p57; (ii) cell lineage phenotype markers: podocalyxin, synaptopodin and GLEPP-1 for podocytes; CD68 for macrophagic epitope; CD3 for T lymphocytes; alpha-smooth muscle actin (alpha-SMA) for myofibroblasts; vimentin for mesenchymal cells; and cytokeratins (CKs) for parietal epithelial cells (PECs); (iii) glomerular fibrosis by labelling collagens I, III and IV, and heat-shock protein 47 (HSP47), a marker of collagen-synthesizing cells; and (iv) co-localization of alpha-SMA, CK and HSP47 using confocal laser microscopy.


RESULTS
The crescent cells proliferated greatly. They did not express p27 and p57. Different cell lineage markers could be identified in crescents: the major component was made of 'dysregulated' PECs negative for CK, followed by PECs positive for CK, macrophagic cells and myofibroblasts. Furthermore, some cells co-expressed CK and alpha-SMA. This latter co-expression suggests a transitional phase in the dynamic phenomenon of EMT. Therefore, proliferative and dysregulated glomerular epithelial cells could be a possible cellular source of myofibroblasts via EMT. In addition, HSP47 labelled many crescent cells and frequently co-localized in CK-positive epithelial cells and in alpha-SMA-positive myofibroblasts, indicating that these cells were involved in glomerular accumulation of collagens.


CONCLUSIONS
EMT is a transient cellular phenomenon present in glomeruli in human PICGN contributing to the formation of myofibroblasts from epithelial cells and to glomerular fibrosis.
Bariety
Jean
J
Université Paris VI, Faculté Broussais-Hotel Dieu, Hôpital Georges Pompidou and INSERM U430, Paris, France.
Hill
Gary S
GS
Mandet
Chantal
C
Irinopoulou
Theano
T
Jacquot
Christian
C
Meyrier
Alain
A
Bruneval
Patrick
P
D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000502:physiology; D004848:Epithelium / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D005921:Glomerulonephritis / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000473:pathology; D008875:Middle Aged