Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton

Takeda, Takeshi; McQuistan, Tammie; Orlando, Robert A.; Farquhar, Marilyn G.

doi:10.1172/jci200112539

Cited by 92 publications

(116 citation statements)

References 37 publications

(21 reference statements)

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“…This might suggest uncoupling of podocalyxin from the actin cytoskeleton as a result of rearrangements of the cytoskeleton. This phenomenon has been described in rat models of proteinuria, in which the complex linking podocalyxin to the actin cytoskeleton is disrupted (19).…”

Section: Discussionmentioning

confidence: 83%

“…Proteins located at the apical part of the podocyte foot process play an important role in ultrafiltration, mainly by maintenance of the negative charge of the membrane domain. The sialoprotein podocalyxin is the most important of these molecules (20) and plays a crucial role in the maintenance of the normal morphology of the podocyte foot processes (19).…”

Section: Discussionmentioning

confidence: 99%

“…The sialoprotein podocalyxin is normally located at the apical part of the foot process. Absence of this protein or changes in its spatial organization also has a detrimental effect on the glo-merular filtration function (18,19). Thus, disruption of the normal gene regulation and protein distribution in the podocyte is related to effacement of foot processes and proteinuria.…”

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confidence: 99%

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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

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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.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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

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“…These differences in function are likely due to differences in the glycosylation state of the large extracellular domain of the protein. The intracellular portion of PODXL is linked to the actin cytoskeleton through interactions with ezrin and likely plays a role in cell morphology (39,40). Full-length PODXL is an integral membrane glycoprotein with a single transmembrane span; however, a soluble form of the protein has also been identified (41).…”

Section: Discussionmentioning

confidence: 99%

The Wilms Tumor Suppressor-1 Target Gene Podocalyxin Is Transcriptionally Repressed by p53

Stanhope-Baker¹,

Kessler²,

et al. 2004

Journal of Biological Chemistry

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Wilms tumor is a pediatric kidney cancer that affects 1 in 10,000 children. The Wilms tumor suppressor-1 (WT1) 1 gene was identified as a tumor suppressor gene based upon the presence of WT1 mutations in a subset (ϳ10 -15%) of Wilms tumor samples (reviewed in Ref. 1). However, the majority of Wilms tumor cases cannot be explained by genetic alteration of the WT1 locus. There may be disruption of biological pathways either upstream or downstream of WT1, or there may be pathways independent of WT1 leading to this type of neoplasm. Several lines of evidence suggest that p53 also plays an important role in the development and/or progression of Wilms tumors. The p53 and WT1 tumor suppressor genes encode transcription factors that have been shown to interact physically and to modulate each other's function in some experimental situations (2). p53 can alter the transcription regulatory activity of WT1. In addition, WT1 stabilizes the p53 protein, alters its activity as a transcription factor, and prevents p53-induced apoptosis (2, 3). Physical and functional interaction has also been observed between the p53 family members p73 and p63 and WT1 (4). Further evidence for biologically relevant interaction between WT1 and p53 includes the fact that the majority of Wilms tumors develop in the presence of wild-type p53 (5). This is in contrast to adult onset human tumors, in which p53 mutations are frequently observed (ϳ50%). The small subset of Wilms tumors that do harbor p53 mutations develop into much more aggressive anaplastic tumors (between 3 and 7% of the total) that are characterized by unfavorable histology, increased metastasis, chemoresistance, and poor prognosis (6 -9). Moreover, Li-Fraumeni patients carrying germ-line p53 mutations are predisposed to development of Wilms tumors (10), and Wilms tumors are one of a small number of cancers that are specifically associated with such mutations (11). To better understand the involvement of both p53 and WT1 in pathways leading to Wilms tumorigenesis, we have used cDNA microarrays to profile gene expression changes dependent upon the activity of these two factors.To accomplish this, we developed strategies to alter the function of WT1 and p53 in a Wilms tumor cell line, WiT49. This cell line is characteristic of anaplastic Wilms tumors in that it expresses wild-type WT1 and mutant p53. We have previously shown that WT1 activity can be effectively abrogated in WiT49 cells by expression of a naturally occurring dominant-negative mutant version of the protein (DDS5) (12). To restore wild-type p53 function in WiT49 cells, we made use of the small molecule compound CP-31398 developed by Pfizer. CP-31398 was originally shown to stabilize the p53 protein with mutation at codon 173, 175, 249, or 273 in the wild-type conformation and to allow its transcriptional and tumor suppressor functions (13). More recently, it has been shown that CP-31398 can stabilize the wild-type p53 protein as well (14 -16). We found here that CP-31398 restores activity to the codon 248 mutant p53 prese...

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“…71 Upon phosphorylation, ezrin links the plasma membrane to actin cytoskeleton, and also interacts with transmembrane proteins. Notably, podocalyxin binds to actin through ezrin, 72 and the antigen recognized by 84 mAb is a podocalyxin-like protein. 51 In the case of cells treated with 84 mAb 52 and KID3/RAV12, 48 a disruption of the actin cytoskeleton was observed.…”

confidence: 99%

Lonely killers

Fernández-Marrero

López‐Requena²

2011

mAbs

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Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton

Cited by 92 publications

References 37 publications

Expression of Podocyte-Associated Molecules in Acquired Human Kidney Diseases

Expression of Podocyte-Associated Molecules in Acquired Human Kidney Diseases

The Wilms Tumor Suppressor-1 Target Gene Podocalyxin Is Transcriptionally Repressed by p53

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