title: Extensive podocyte loss triggers a rapid parietal epithelial cell response.
abstract: Damage to podocytes is a central pathomechanism of proteinuric kidney disease. However, it is not fully understood how podocyte injury evolves to progressive glomerulopathies such as FSGS or collapsing glomerulopathy. In particular, the role of parietal epithelial cells remains controversial. Here, we show that adriamycin induces DNA damage and podocyte lysis in mice without evidence of autophagy, endoplasmic reticulum stress, or necroptosis. After extensive podocyte loss, activated parietal cells mediated tuft re-epithelialization by two distinct mechanisms. In the majority of glomeruli, vacuolized parietal epithelial cells attached to denuded glomerular basement membrane and, occasionally, disengaged from the parietal basement membrane. Less frequently, parietal epithelial cells covered the denuded visceral basement membrane via formation of proliferative pseudocrescents. Notably, "visceralized" parietal epithelial cells did not express vascular endothelial growth factor but upregulated hypoxia-inducible factor 1 expression. The presence of visceralized parietal epithelial cells in sclerosing and collapsing lesions in a kidney biopsy from a patient with diabetes underscores the human relevance of our findings. In conclusion, repopulation of the glomerular tuft by parietal cells may represent a compensatory response to extensive podocyte loss. Our results suggest, however, that visceralized parietal epithelial cells cannot induce revascularization of the hyalinized tuft, resulting in hypoxic cell death and irreversible destruction of the glomerulus.
authors: Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors: Samy
authors: S
authors: Hakroush
authors: Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors: Angelika
authors: A
authors: Cebulla
authors: Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors: Thomas
authors: T
authors: Schaldecker
authors: Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors: Daniel
authors: D
authors: Behr
authors: Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors: Peter
authors: P
authors: Mundel
authors: Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts aweins@partners.org.
authors: Astrid
authors: A
authors: Weins
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000473:pathology* / Q000502:physiology; D005260:Female; D050533:Glomerular Basement Membrane / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology* / Q000473:pathology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000473:pathology*; D011507:Proteinuria / Q000139:chemically induced* / Q000473:pathology
chemical_list: D051793:Hypoxia-Inducible Factor 1