Podocytopenia and disease severity in IgA nephropathy

Lemley, Kevin V.; Lafayette, Richard A.; Safai, Massy; Derby, Geraldine C.; Blouch, Kristina; Squarer, A; Myers, Bryan D.

doi:10.1046/j.1523-1755.2002.00269.x

Cited by 264 publications

(214 citation statements)

References 23 publications

(6 reference statements)

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…It is well-recognized that podocyte loss initiates and promotes glomerular disease progression (16,20). While cultured podocytes lack normal cell-cell podocyte contacts, including slit diaphragms, our results are compatible with a feed-forward model in which normal cell-cell contact between podocytes initiates signals that maintain a differentiated phenotype, and conversely loss of these signals degrades podocyte phenotype.…”

Section: F808 Cell-cell Contact Regulates Podocyte Gene Expressionsupporting

confidence: 86%

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Sakairi

Abe

Jat

et al. 2010

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

We transformed mouse podocytes by ectopic expression of cyclin-dependent kinase 4 (CDK4). Compared with podocytes transformed with a thermo-sensitive SV40 large T antigen mutant tsA58U19 (tsT podocytes), podocytes transformed with CDK4 (CDK4 podocytes) exhibited significantly higher expression of nephrin mRNA. Synaptopodin mRNA expression was significantly lower in CDK4 podocytes and in tsT podocytes under growth-permissive conditions (33°C) compared with tsT podocytes under growth-restricted conditions (37°C), which suggests a role for cell cycle arrest in synaptopodin mRNA expression. Confluent CDK4 podocytes showed significantly higher mRNA expression levels for nephrin, synaptopodin, Wilms tumor 1, podocalyxin, and P-cadherin compared with subconfluent cultures. We carried out experiments to clarify roles of various factors in the confluent podocyte cultures; our findings indicate that cell-cell contact promotes expression of five podocyte marker genes studied, that cellular quiescence increases synaptopodin and podocalyxin mRNA expression, and that soluble factors play a role in nephrin mRNA expression. Our findings suggest that CDK4 podocytes are useful tools to study podocyte biology. Furthermore, the role of cell-cell contact in podocyte gene expression may have relevance for podocyte function in vivo.cyclin-dependent kinase 4; SV40 large T antigen; nephrin; synaptopodin; Wilms tumor-1; P-cadherin PODOCYTE CULTURES, ESPECIALLY podocyte cell lines transformed by thermosensitive SV40 large T antigen (SV40 T), have been widely used to study podocyte biology (19,25). However, as we recently reported in studies on a generation of mouse and human podocyte cell lines, podocytes transformed by thermosensitive SV40 T (tsT) exhibit phenotypic differences compared with podocytes in vivo, with reduced expression of certain differentiation marker genes (13, 24).Cyclin-dependent kinase 4 (CDK4), a catalytic subunit of the cyclin D-CDK4 serine/threonine kinase complex, is a critical regulator of the cell cycle. CDK4 is the first kinase activated by mitogenic signals. The kinase activity of CDK4 is specifically involved in progression through G1, via phosphorylation of retinoblastoma (Rb) family members (4). Recently, Ramirez et al. (22) immortalized human bronchial epithelial cells by ectopic expression of CDK4 and human telomerase (hTERT). Microarray analysis showed that CDK4/hTERTimmortalized cells showed significantly different gene expression profiles compared with cells immortalized with human papiloma viral oncoproteins E6/E7 or SV40T and that CDK4-transformed cells clustered with primary bronchial epithelial cells. In addition, recent studies showed that cells immortalized with CDK4 are useful tools to study physiology and pathophysiology (8,23,30).We set out to develop an alternative approach to transforming podocytes by comparing the phenotype among primary cells, CDK4-transformed podocytes (CDK4-podocytes) and thermosensitive SV40 T mutant tsA58U19 (tsT-podocytes). We found that CDK4-podocytes and tsT-podocyt...

show abstract

Section: F808 Cell-cell Contact Regulates Podocyte Gene Expressionsupporting

confidence: 86%

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Sakairi

Abe

Jat

et al. 2010

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…The observation that downregulation of nephrin protein is paralleled by foot process effacement is in line with results from a study by Huh et al (49) and Wernerson et al (50), which suggests that not the quantity of nephrin between adjacent foot processes is different but that merely the total glomerular amount of nephrin is decreased as a result of foot process effacement. The decreased protein staining of nephrin, podocin, and podocalyxin might also be explained by a reduction of podocytes, as has been observed in several diseases (51,52). Furthermore, the accessibility of the antigen might be diminished.…”

Section: Discussionmentioning

confidence: 79%

Expression of Podocyte-Associated Molecules in Acquired Human Kidney Diseases

Koop¹,

Eikmans²,

Baelde³

et al. 2003

Journal of the American Society of Nephrology

272

200

View full text Add to dashboard Cite

Abstract. Proteinuria is a poorly understood feature of many acquired renal diseases. Recent studies concerning congenital nephrotic syndromes and findings in genetically modified mice have demonstrated that podocyte molecules make a pivotal contribution to the maintenance of the selective filtration barrier of the normal glomerulus. However, it is unclear what role podocyte molecules play in proteinuria of acquired renal diseases. This study investigated the mRNA and protein expression of several podocyte-associated molecules in acquired renal diseases. Forty-eight patients with various renal diseases were studied, including minimal change nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis, and diabetic nephropathy, together with 13 kidneys with normal glomerular function. Protein levels of nephrin, podocin, CD2-associated protein, and podocalyxin were investigated using quantitative immunohistochemical assays. Real-time PCR was used to determine the mRNA levels of nephrin, podocin, and podoplanin in microdissected glomeruli. The obtained molecular data were related to electron microscopic ultrastructural changes, in particular foot process width, and to clinical parameters. In most acquired renal diseases, except in IgA nephropathy, a marked reduction was observed at the protein levels of nephrin, podocin, and podocalyxin, whereas an increase of the glomerular mRNA levels of nephrin, podocin, and podoplanin was found, compared with controls. The mean width of the podocyte foot processes was inversely correlated with the protein levels of nephrin (r ϭ Ϫ0.443, P Ͻ 0.05), whereas it was positively correlated with podoplanin mRNA levels (r ϭ 0.468, P Ͻ 0.05) and proteinuria (r ϭ 0.585, P ϭ 0.001). In the diseases studied, the decrease of slit diaphragm proteins was related to the effacement of foot processes and coincided with a rise of the levels of the corresponding mRNA transcripts. This suggests that the alterations in the expression of podocyte-associated molecules represent a compensatory reaction of the podocyte that results from damage associated with proteinuria.

show abstract

“…[27][28][29][30][31][32] This is, in part, because of the difficulty in counting podocytes and the lack of consensus on how to accurately count them. Lemley et al 11 recently compared five methods for estimating podocyte number and recommended that the design-based dissector/optical fractionator method was the optimum technique when sufficient kidney tissue was available.…”

mentioning

confidence: 99%

Podocyte Number in Children and Adults

Puelles

Douglas-Denton

Cullen‐McEwen

et al. 2015

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Increases in glomerular size occur with normal body growth and in many pathologic conditions. In this study, we determined associations between glomerular size and numbers of glomerular resident cells, with a particular focus on podocytes. Kidneys from 16 male Caucasian-Americans without overt renal disease, including 4 children (#3 years old) to define baseline values of early life and 12 adults ($18 years old), were collected at autopsy in Jackson, Mississippi. We used a combination of immunohistochemistry, confocal microscopy, and design-based stereology to estimate individual glomerular volume (IGV) and numbers of podocytes, nonepithelial cells (NECs; tuft cells other than podocytes), and parietal epithelial cells (PECs). Podocyte density was calculated. Data are reported as medians and interquartile ranges (IQRs). Glomeruli from children were small and contained 452 podocytes (IQR=335-502), 389 NECs (IQR=265-498), and 146 PECs (IQR=111-206). Adult glomeruli contained significantly more cells than glomeruli from children, including 558 podocytes (IQR=431-746; P,0.01), 1383 NECs (IQR=998-2042; P,0.001), and 367 PECs (IQR=309-673; P,0.001). However, large adult glomeruli showed markedly lower podocyte density (183 podocytes per 10 6 mm 3 ) than small glomeruli from adults and children (932 podocytes per 10 6 mm 3 ; P,0.001). In conclusion, large adult glomeruli contained more podocytes than small glomeruli from children and adults, raising questions about the origin of these podocytes. The increased number of podocytes in large glomeruli does not match the increase in glomerular size observed in adults, resulting in relative podocyte depletion. This may render hypertrophic glomeruli susceptible to pathology.

show abstract

Podocytopenia and disease severity in IgA nephropathy

Abstract: Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder.

Cited by 264 publications

References 23 publications

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Expression of Podocyte-Associated Molecules in Acquired Human Kidney Diseases

Podocyte Number in Children and Adults

Contact Info

Product

Resources

About