Synaptopodin Protects Against Proteinuria by Disrupting Cdc42:IRSp53:Mena Signaling Complexes in Kidney Podocytes

Yanagida-Asanuma, Etsuko; Asanuma, Katsuhiko; Kim, Kwanghee; Donnelly, Mary; Choi, Hoon Young; Chang, Jae Hyung; Suetsugu, Shiro; Tomino, Yasuhiko; Takenawa, Tadaomi; Faul, Christian; Mündel, Peter

doi:10.2353/ajpath.2007.070075

Cited by 149 publications

(161 citation statements)

References 48 publications

(111 reference statements)

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“…Interestingly, the SH3 domain of IRSp53 has been shown to mediate the interaction with Eps8 and to enhance Eps8-Abi1-Sos-1 signaling to Rac1 (Funato et al, 2004). More recently, Yanagida-Asanuma and colleagues showed that synaptopodin, an actin-associated protein, binds directly to IRSp53 and suppresses Cdc42-IRSp53-Mena-initiated formation of filopodia by blocking the binding of Cdc42 and Mena to IRSp53 in kidney podocytes (Yanagida-Asanuma et al, 2007). This suggests that the interactions of IRSp53 alone are complex and warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Membrane targeting of WAVE2 is not sufficient for WAVE2-dependent actin polymerization: a role for IRSp53 in mediating the interaction between Rac and WAVE2

Abou-Kheir

Isaac

Yamaguchi

et al. 2008

Journal of Cell Science

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Section: Discussionmentioning

confidence: 99%

Membrane targeting of WAVE2 is not sufficient for WAVE2-dependent actin polymerization: a role for IRSp53 in mediating the interaction between Rac and WAVE2

Abou-Kheir

Isaac

Yamaguchi

et al. 2008

Journal of Cell Science

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“…However, some of these patients do respond to treatment with corticosteroids plus CsA. In these cases, it is interesting to note that the targets of CsA in glomerular disorders are not only T-or Bcells but also the podocyte cytoskeleton via inhibition of synaptopodin phosphorylation [14]. Stabilization of the cytoskeleton might be the explanation for the effects of add-on CsA observed in the APN CsA study [9].…”

Section: Limitations Of the Saadeh Studymentioning

confidence: 99%

Dosing of glucocorticosteroids in nephrotic syndrome

Mehls

Hoyer

2011

Pediatr Nephrol

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SummaryPharmacodynamic actions and molecular mechanisms of corticosteroids in patients with nephrotic syndrome (NS) are poorly understood. The role of immunosuppressive and of direct stabilizing effects on the podocyte cytoskeleton needs to be defined. Without precise knowledge of the pathogenesis, optimal dosing cannot be established. The finding of Saadeh et al. [1] that dosing of glucocorticoids per body surface area is superior to dosing per kilogram body weight (BW) in terms of reducing the recurrence rate of NS is interesting; however, an overriding effect of age cannot be ruled out.It is unlikely that all patients with an initial presentation of NS require the same amount of glucocorticoid treatment as patients with recurrent disease. In the future, it may be more important to establish individual treatment strategies than to adapt high doses of glucocorticoids according to anthropometric measurements. : while the initial response was not influenced by such 'underdosing', the frequency of relapses during the first 6 months appeared to be higher in this relatively 'underdosed' group. This result is an argument for a prednisone dosing regimen based on body surface area, at least for the initial and relapse treatment of NS in children. The most important implication of this type of reasoning-if it is indeed correct-is that the relatively higher dose calculated on the basis of body surface area is the optimal dose for achieving the therapeutic effect. The differences in doses would then explain the observed variation in therapeutic results. However, important questions must be answered before this treatment regimen can be approved on the basis of pathophysiology and pharmacology. Therefore, we would like to extend the discussion on dosing to poorly understood fundamental aspects of glucocorticoid actions in NS, which may be fruitful fields for basic and clinical research in pediatric nephrology. Scope of the problemIs 60 mg prednisone/m 2 /day the approved optimal treatment dose for the initial manifestation of NS?In the 1970s, the members of the International Study of Kidney Disease in Children (ISKDC) Study Group agreed on a dose of 60 mg/m 2 /day prednisone for 4 weeks followed by 40 mg/m 2 /day as the standard treatment for the initial manifestation of NS as the basis for seminal international prospective studies. The agreement was mainly based on personal clinical experience and a review of the literature, but at that time no dose-finding studies had

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“…43 In addition, Asanuma et al demonstrated that synaptopodin plays an essential role in the formation of focal contacts via the inhibition of Smurf1-mediated polyubiquitination of RhoA. 38 Specifically, targeted synaptopodin gene knockdown in podocytes promoted derangement of focal contact assembly, podocyte dysmotility, and enhanced RhoA polyubiquitination.…”

Section: R394tmentioning

confidence: 99%

A Novel Missense Mutation of Wilms’ Tumor 1 Causes Autosomal Dominant FSGS

Hall¹,

Gbadegesin

Lavin

et al. 2015

Journal of the American Society of Nephrology

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FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1 R458Q overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1 R458Q mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.

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Synaptopodin Protects Against Proteinuria by Disrupting Cdc42:IRSp53:Mena Signaling Complexes in Kidney Podocytes

Cited by 149 publications

References 48 publications

Membrane targeting of WAVE2 is not sufficient for WAVE2-dependent actin polymerization: a role for IRSp53 in mediating the interaction between Rac and WAVE2

Membrane targeting of WAVE2 is not sufficient for WAVE2-dependent actin polymerization: a role for IRSp53 in mediating the interaction between Rac and WAVE2

Dosing of glucocorticosteroids in nephrotic syndrome

A Novel Missense Mutation of Wilms’ Tumor 1 Causes Autosomal Dominant FSGS

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