Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies

Barisoni, Laura; Mokrzycki, Michele H.; Sablay, Leonada; Nagata, Michio; Yamase, Harold; Mündel, Peter

doi:10.1046/j.1523-1755.2000.00149.x

Cited by 172 publications

(145 citation statements)

References 22 publications

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“…Many studies have suggested that epithelial hyperplasia in various glomerular diseases is characterized by cells that stain negatively for podocyte markers (eg synaptopodin and PHM-5) and CKIs, stain positively for cytokeratin, and occasionally stain positively for CDK2, Ki-67 and cyclins (E, A, B1). 7,25,[36][37][38] We now provide evidence of PCNA, c-Myc and E2F1 overexpression in these lesions against a background of absent p27 kip1 and p57 kip2 expression in IgAN. Novel findings included a weak to moderate expression of p21 waf1 and p16 ink4a in these cellular lesions, in addition to the colocalization of p21 waf1 with PCNA in these epithelial lesions.…”

Section: Discussionmentioning

confidence: 53%

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Qiu

Sinniah

Hsu

2004

Laboratory Investigation

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The activities of cell cycle regulatory proteins have been reported to be associated with the development of pathological lesions in glomerulonephritis. To assess the cellular mechanisms underlying the mesangial cell proliferation and glomerulosclerosis in progressive human IgA nephropathy (IgAN), we examined the expression of E2F1, Rb, c-Myc, proliferating cell nuclear antigen (PCNA), cyclins (D1, E and A), cyclindependent kinase 2 (CDK2) and CDK inhibitors (p21 waf1 , p27 kip1 , 57 kip2 and p16 ink4a ) by immunohistochemistry in renal biopsy specimens. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was also performed to detect the presence of apoptosis. In total, 51 cases of IgAN were categorized into four subgroups according to histological severity. A dramatic upregulation of E2F1 expression in mesangial cells was identified in proliferating glomeruli, which correlated well with the proliferation index. High endogenous expression of p27 kip1 and p57 kip2 by podocytes in normal glomeruli and glomeruli with minor lesions was observed to decrease in proliferating and sclerosing glomeruli; this pattern displayed a strong inverse correlation with the mean glomerulosclerosis score and the index of glomerular lesion. Increased apoptotic activity was identified in progressive glomerular lesions of advanced IgAN, which correlated with the proliferative activity in these lesions as assessed by total expression levels of PCNA and CDK2 in glomeruli, E2F1 expression levels in the mesangium, cyclin D1 expression levels in endothelium and the c-Myc glomerular staining score. Our results suggest that the onset and magnitude of mesangial cell proliferation and glomerulosclerosis is associated with the upregulation of E2F1 by mesangial cells and the downregulation of p27 kip1 and p57 kip2 by glomerular epithelial cells. The cell type-specific and coordinated regulation of proliferative and proapoptotic activities of cell cycle regulatory proteins may play an important role in mediating progressive glomerular injury in human IgAN. Laboratory Investigation (2004) 84, 1112-1125, advance online publication, 21 June 2004 doi:10.1038/labinvest.3700144 Keywords: IgA nephropathy; cell cycle regulatory protein; mesangial cell proliferation; glomerulosclerosis; apoptosis Cell cycle regulatory proteins (CCPs) govern not only cellular hypertrophy and proliferation, but also cellular apoptosis and differentiation. Mounting evidence has emerged that indicates a close link between cell cycle regulation and the development of histopathological lesions in glomerular diseases. 1,2 In the experimental model of mesangial proliferative anti-Thy1.1 nephritis, increased expression of cyclins A, D1 and cyclin-dependent kinase 2 (CDK2) by mesangial cells in association with decreased high endogenous levels of CDK inhibitor (CKI) p27 kip1 by glomerular epithelial cells (GECs), were required for mesangial cell proliferation. [3][4][5] The increased glomerular activity of CDK2 could be inhibited by the CDK antagonist r...

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Section: Discussionmentioning

confidence: 53%

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Qiu

Sinniah

Hsu

2004

Laboratory Investigation

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“…However, podocytes in adults are known to have a limited potential for cell proliferation (22,23). In collapsing FSGS, dysregulated podocytes lose the expression of specific markers and seem to proliferate in a manner reminiscent of localized benign neoplastic growth (24). In a transgenic mouse model, genetic reduction of the expression of WT-1, a transcription factor expressed exclusively in podocytes in the kidneys of adult mice, was sufficient to induce cell proliferation in dysregulated podocytes and resulted in the formation of cellular crescents (25).…”

Section: Discussionmentioning

confidence: 99%

Podocytes Populate Cellular Crescents in a Murine Model of Inflammatory Glomerulonephritis

Moeller

Soofi²,

Hartmann

et al. 2004

Journal of the American Society of Nephrology

168

142

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Abstract. Cellular crescents are a defining histologic finding in many forms of inflammatory glomerulonephritis. Despite numerous studies, the origin of glomerular crescents remains unresolved. A genetic cell lineage-mapping study with a novel transgenic mouse model was performed to investigate whether visceral glomerular epithelial cells, termed podocytes, are precursors of cells that populate cellular crescents. The podocytespecific 2.5P-Cre mouse line was crossed with the ROSA26 reporter line, resulting in irreversible constitutive expression of ␤-galactosidase in doubly transgenic 2.5P-Cre/ROSA26 mice. In these mice, crescentic glomerulonephritis was induced with a previously described rabbit anti-glomerular basement membrane antiserum nephritis approach. Interestingly, ␤-galactosidase-positive cells derived from podocytes adhered to the parietal basement membrane and populated glomerular crescents during the early phases of cellular crescent formation, accounting for at least one-fourth of the total cell mass. In cellular crescents, the proliferation marker Ki-67 was expressed in ␤-galactosidase-positive and ␤-galactosidase-negative cells, indicating that both cell types contributed to the formation of cellular crescents through proliferation in situ. Podocyte-specific antigens, including WT-1, synaptopodin, nephrin, and podocin, were not expressed by any cells in glomerular crescents, suggesting that podocytes underwent profound phenotypic changes in this nephritis model.

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“…In either case, these results strongly suggest that a link exists between the regulation of cytoskeletal function and nephrin expression. Expression of the transcription factor WT-1, a podocyte-lineage marker, has been previously shown to be downregulated in some nonfamilial forms of collapsing and noncollapsing FSGS, thereby suggesting a reversion of the podocyte to a more immature/proliferating phenotype (4,41,42). However, we now show that WT-1 mRNA levels and immunofluorescence of synaptopodin (data not shown), another podocytespecific marker, were not significantly different between the three groups of mice, thereby suggesting that despite the reduced nephrin expression, these cells maintained a somewhat differentiated phenotype.…”

Section: Discussionmentioning

confidence: 99%

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

Michaud

Lemieux²,

Dubé

et al. 2003

Journal of the American Society of Nephrology

143

124

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Abstract. Mutations in the gene encoding ␣-actinin-4 (ACTN4), an actin crosslinking protein, are associated with a form of autosomal dominant focal segmental glomerulosclerosis (FSGS). To better study its progression, a transgenic mouse model was developed by expressing murine ␣-actinin-4 containing a mutation analogous to that affecting a human FSGS family in a podocyte-specific manner using the murine nephrin promoter. Consistent with human ACTN4-associated FSGS, which shows incomplete penetrance, a proportion of the transgenic mice exhibited significant albuminuria (8 of 18), while the overall average systolic BP was elevated in both proteinuric and non-proteinuric ACTN4-mutant mice. Immunofluorescence confirmed podocyte-specific expression of mutant ␣-actinin-4, and real-time RT-PCR revealed that HA-ACTN4 mRNA levels were higher in proteinuric versus non-proteinuric ACTN4-mutant mice. Only proteinuric mice exhibited histologic features consistent with human ACTN4-associated FSGS, including segmental sclerosis and tuft adhesion of some glomeruli, tubular dilatation, mesangial matrix expansion, as well as regions of podocyte vacuolization and foot process fusion. Consistent with such podocyte damage, proteinuric ACTN4-mutant kidneys exhibited significantly reduced mRNA and protein levels of the slit diaphragm component, nephrin. This newly developed mouse model of human ACTN4-associated FSGS suggests a cause-and-effect relationship between actin cytoskeleton dysregulation by mutant ␣-actinin-4 and the deterioration of the nephrin-supported slit diaphragm complex.

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Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies

Cited by 172 publications

References 22 publications

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Podocytes Populate Cellular Crescents in a Murine Model of Inflammatory Glomerulonephritis

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

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