Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Parietal Cell Hyperplasia in a Murine Model of Cellular/Collapsing Focal Segmental Glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is a progressive renal disease, and the glomerular visceral cell hyperplasia typically observed in cellular/collapsing FSGS is an important pathological factor in disease progression. However, the cellular features that promote FSGS currently remain obscure. To determine both the origin and phenotypic alterations in hyperplastic cells in cellular/collapsing FSGS, the present study used a previously described FSGS model in p21-deficient mice with visceral cell hyperplasia and identified the podocyte lineage by genetic tagging. The p21-deficient mice with nephropathy showed significantly higher urinary protein levels, extracapillary hyperplastic indices on day 5, and glomerular sclerosis indices on day 14 than wild-type controls. X-gal staining and immunohistochemistry for podocyte and parietal epithelial cell (PEC) markers revealed progressive podocytopenia with capillary collapse accompanied by PEC hyperplasia leading to FSGS. In our investigation, non-tagged cells expressed neither WT1 nor nestin. Ki-67, a proliferation marker, was rarely associated with podocytes but was expressed at high levels in PECs. Both terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and electron microscopy failed to show evidence of significant podocyte apoptosis on days 5 and 14. These findings suggest that extensive podocyte loss and simultaneous PEC hyperplasia is an actual pathology that may contribute to the progression of cellular/collapsing FSGS in this mouse model. Additionally, this is the first study to demonstrate the regulatory role of p21 in the PEC cell cycle. (Am J

Recent advances of animal model of focal segmental glomerulosclerosis

“…Although relatively little attention has been paid to morphologic subtypes of FSGS in animal models, some models were found to mimic certain variants of human FSGS. Collapsing variant has been most actively studied in terms of the pathogenesis of FSGS, focusing on the role of parietal epithelial cells [87]. In addition, perihilar variant was observed in renal ablation models, and tip variant was associated with intraglomerular shear reflecting the underlying pathogenetic mechanisms of these variants [88].…”

Renal Progenitor Cells Contribute to Hyperplastic Lesions of Podocytopathies and Crescentic Glomerulonephritis

“…50 In contrast, an abnormally high regenerative activity by resident renal progenitors would result in hyperplasia, similar to the hypertrophic scarring observed in skin keloids. Reasons underlying this different response might be related to the type of injury or to the different genetic background of patients, as suggested by a recent study 52 demonstrating that induction of a podocyte damage leads to glomerular injury with segmental lesions and mild intraglomerular proliferation of PECs in wild-type mice but to a complete histologic pattern of collapsing glomerulopathy related to high PECs proliferation in mice knockout for the cell cycle inhibitor p21.…”

Glomerular Epithelial Stem Cells

“…75,80 Thus, glomerular epithelial stem cells may proliferate and migrate from the urinary pole of the Bowman's capsule toward the tuft in an attempt to replace the podocytes lost in response to heavy proteinuria, generating the tip lesion ( Figure 3B). Taken together, the results of these recent studies suggest the clinicopathologic features of different glomerular disorders more likely represent distinct patterns of injury or repair rather than diseases.…”

“…Accordingly, a recent study demonstrates that podocyte damage leads to glomerular injury with a complete histologic pattern of collapsing glomerulopathy related to high parietal epithelial cell proliferation in mice with null alleles for the cell cycle inhibitor, p21, compared with segmental lesions and mild intraglomerular proliferation in wild-type mice. 75 Finally, glomerular epithelial stem cells are also the main constituents of the tip lesion. 70 Interestingly, the tip lesion is described in several proteinuric conditions, including FSGS, membranous nephropathy, 76 postinfectious glomerulonephritis, 77 and diabetic nephropathy.…”