Tracing the Origin of Glomerular Extracapillary Lesions from Parietal Epithelial Cells

Abstract

Cellular lesions form in Bowman's space in both crescentic glomerulonephritis and collapsing glomerulopathy. The pathomechanism and origin of the proliferating cells in these lesions are unknown. In this study, we examined proliferating cells by lineage tracing of either podocytes or parietal epithelial cells (PECs) in the nephrotoxic nephritis model of inflammatory crescentic glomerulonephritis. In addition, we traced the fate of genetically labeled PECs in the Thy-1.1 transgenic mouse model of collapsing glomerulopathy. In both models, cellular bridges composed of PECs were observed between Bowman's capsule and the glomerular tuft. Genetically labeled PECs also populated larger, more advanced cellular lesions. In these lesions, we detected de novo expression of CD44 in activated PECs. In contrast, we rarely identified genetically labeled podocytes within the cellular lesions of crescentic glomerulonephritis. In conclusion, PECs constitute the majority of cells that compose early extracapillary proliferative lesions in both crescentic glomerulonephritis and collapsing glomerulopathy, suggesting similar pathomechanisms in both diseases.

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

“…From our previous findings in murine experimental crescentic glomerulonephritis and FSGS 10,12 it was anticipated to detect CD44 þ PECs in FSGS lesions and along Bowman's capsule of affected glomeruli. However, in 94% of the CD44 þ glomeruli, CD44 staining was restricted to the visceral PECs ( Figure 3D).…”

“…9e11 On an initial glomerular injury, PECs on Bowman's capsule can become activated. 10,12 Activated PECs have a distinct phenotype, such as increased migration, proliferation, and/or matrix deposition of PECs. In general, activated PECs have a larger cuboidal cytoplasm with enlarged nuclei and form a thickened parietal basement membrane secondary to matrix production.…”

“…9 Activated PECs can be recognized by the de novo expression of CD44 as found in experimental models of FSGS and crescentic glomerulonephritis and in biopsies of human patients with FSGS and crescentic glomerulonephritis. 10,12,13 In experimental rodents it has been unequivocally found that in the process of development glomerulosclerosis, activated PECs invade the glomerular tuft at the site of an adhesion and cover long stretches of the tuft surface. In this process activated PECs deposit matrix.…”

The Pathogenesis of Lupus Nephritis

“…79 In addition, cellular glomerular crescent formation results from activation of parietal epithelial cells that fill the urinary space by uncoordinated proliferation. 80,81 This process can be triggered by glomerular basement membrane breaks that allow plasma leakage into Bowman's space, where mitogenic plasma components such as fibrinogen trigger hyperproliferation of the parietal epithelial cells. 82 At later stages, the parietal epithelial cells lose their polarity and produce matrix all around themselves, which creates honeycomb matrix deposits in Bowman's space that turn cellular crescents into fibrocellular crescents with glomerulosclerosis, also referred to as class VI LN.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…A novel paradigm showed that the inconspicuous cells lining Bowman's capsule, the parietal epithelial cells, are crucially involved in the pathogenesis of not only crescentic glomerulonephritis but also most types of glomerulosclerosis (119)(120)(121)(122)(123)(124) (Figure 2). The identification of specific molecules resulting in activation of these cells might lead to novel therapeutic options in glomerulosclerosis.…”