title: The direction and role of phenotypic transition between podocytes and parietal epithelial cells in focal segmental glomerulosclerosis.
abstract: Focal segmental glomerulosclerosis (FSGS) is a podocyte disease. Among the various histologies of FSGS, active epithelial changes, hyperplasia, as typically seen in the collapsing variant, indicates disease progression. Using a podocyte-specific injury model of FSGS carrying a genetic podocyte tag combined with double immunostaining by different sets of podocytes and parietal epithelial cell (PEC) markers [nestin/Pax8, Wilms' tumor-1 (WT1)/claudin1, and podocalyxin/Pax2], we investigated the direction of epithelial phenotypic transition and its role in FSGS. FSGS mice showed progressive proteinuria and renal dysfunction often accompanied by epithelial hyperplasia, wherein 5-bromo-4-chloro-3-indoyl β-d-galactoside (X-gal)-positive podocyte-tagged cells were markedly decreased. The average numbers of double-positive cells in all sets of markers were significantly increased in the FSGS mice compared with the controls. In addition, the average numbers of double-positive cells for X-gal/Pax8, nestin/Pax8 and podocalyxin/Pax2 staining in the FSGS mice were comparable, whereas those of WT1/claudin1 were significantly increased. When we divided glomeruli from FSGS mice into those with FSGS lesions and those without, double-positive cells tended to be more closely associated with glomeruli without FSGS lesions compared with those with FSGS lesions. Moreover, the majority of double-positive cells appeared to be isolated and very rarely associated with FSGS lesions (1/1,997 glomeruli). This study is the first to show the incidence and localization of epithelial cells with phenotypical changes in FSGS using a genetic tag. The results suggest that the major direction of epithelial phenotypic transition in cellular FSGS is from podocytes to PECs and that these cells were less represented in the active lesions of FSGS.
authors.affiliation: Kidney and Vascular Pathology, Faculty of Medicine, Univ. of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8577, Japan. nagatam@md.tsukuba.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ueno
authors.forename: Namiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hara
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Takashima
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.forename: Michio
authors.initials: M
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D015415:Biomarkers; D002454:Cell Differentiation; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology; D004848:Epithelium / Q000473:pathology; D005098:Exotoxins / Q000633:toxicity; D005786:Gene Expression Regulation; D005819:Genetic Markers; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit; D051379:Mice; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000166:cytology* / Q000502:physiology; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D015415:Biomarkers; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D005098:Exotoxins; D005819:Genetic Markers; D053645:Interleukin-2 Receptor alpha Subunit; D064231:Nestin; D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C499496:Pax8 protein, mouse; D012795:Sialoglycoproteins; D025721:WT1 Proteins; C001643:podocalyxin
keywords: cellular FSGS; focal segmental glomerulosclerosis; parietal epithelial cell; phenotypic transition; podocyte