IQGAP1 Interacts with Components of the Slit Diaphragm Complex in Podocytes and Is Involved in Podocyte Migration and Permeability In Vitro

Rigothier, Claire; Auguste, Patrick; Welsh, Gavin I.; Lepreux, Sébastien; Déminière, C.; Mathieson, Peter W.; Saleem, Moin A.; Ripoche, Jean; Combe, Christian

doi:10.1371/journal.pone.0037695

Cited by 31 publications

(20 citation statements)

References 45 publications

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“…Although the question of whether motile podocytes induce proteinuria and renal damage is still controversial, 8,41 it is widely accepted that the reorganization of actin cytoskeleton is necessary for podocyte migration. 40,41,48 Thus, the results of our experiments show that SIRT1 is required for the appropriate reorganization of actin cytoskeleton in podocytes. SIRT1 belongs to the HDAC family, which acts to deacetylate proteins and histones and controls epigenetic changes and protein functions.…”

Section: Discussionsupporting

confidence: 51%

“…Because the cellular motility of podocytes is dependent on their dynamic assembly of actin, [38][39][40][41] we hypothesized that podocyte migration ability is attenuated when the regulation of actin cytoskeleton is disorganized by SIRT1 inhibition. To address this, we examined the change in cellular motility by scratch assay.…”

Section: Podocyte Motility Is Reduced By Sirt1 Inhibitionmentioning

confidence: 99%

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Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

Motonishi¹,

Nangaku²,

Wada³

et al. 2015

Journal of the American Society of Nephrology

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Recent studies have highlighted the renoprotective effect of sirtuin1 (SIRT1), a deacetylase that contributes to cellular regulation. However, the pathophysiologic role of SIRT1 in podocytes remains unclear. Here, we investigated the function of SIRT1 in podocytes. We first established podocyte-specific Sirt1 knockout (SIRT1 pod2/2 ) mice. We then induced glomerular disease by nephrotoxic serum injection. The increase in urinary albumin excretion and BUN and the severity of glomerular injury were all significantly greater in SIRT1 pod2/2 mice than in wild-type mice. Western blot analysis and immunofluorescence showed a significant decrease in podocyte-specific proteins in SIRT1 pod2/2 mice, and electron microscopy showed marked exacerbation of podocyte injury, including actin cytoskeleton derangement in SIRT1 pod2/2 mice compared with wild-type mice. Protamine sulfate-induced podocyte injury was also exacerbated by podocyte-specific SIRT1 deficiency. In vitro, actin cytoskeleton derangement in H 2 O 2 -treated podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Conversely, this H 2 O 2 -induced derangement was ameliorated by SIRT1 activation. Furthermore, SIRT1 activation deacetylated the actin-binding and -polymerizing protein cortactin in the nucleus and facilitated deacetylated cortactin localization in the cytoplasm. Cortactin knockdown or inhibition of the nuclear export of cortactin induced actin cytoskeleton derangement and dissociation of cortactin from F-actin, suggesting the necessity of cytoplasmic cortactin for maintenance of the actin cytoskeleton. Taken together, these findings indicate that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and thereby, maintaining actin cytoskeleton integrity.

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Section: Discussionsupporting

confidence: 51%

Section: Podocyte Motility Is Reduced By Sirt1 Inhibitionmentioning

confidence: 99%

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

Motonishi¹,

Nangaku²,

Wada³

et al. 2015

Journal of the American Society of Nephrology

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“…Notably, the closely related protein IQGAP1 was also reported to interact with the podocyte cytoskeleton and components of the SDs, including Nephrin, 31 and to control podocyte motility and permeability in vitro. 32 Together with a recent report on downregulation of IQGAP1 in patients with diabetic nephropathy, 33 both IQGAP isoforms may play a particular role in podocyte biology. Future experiments will have to determine whether IQGAP1 and IQGAP2 possess redundant and/or unique functions and how they are possibly linked to acquired and/or hereditary forms of NS in humans.…”

Section: Discussionmentioning

confidence: 86%

The Rho-GTPase binding protein IQGAP2 is required for the glomerular filtration barrier

Sugano

Lindenmeyer

Auberger

et al. 2015

Kidney International

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Podocyte dysfunction impairs the size selectivity of the glomerular filter, leading to proteinuria, hypoalbuminuria, and edema, clinically defined as nephrotic syndrome. Hereditary forms of nephrotic syndrome are linked to mutations in podocyte-specific genes. To identify genes contributing to podocyte dysfunction in acquired nephrotic syndrome, we studied human glomerular gene expression data sets for glomerular-enriched gene transcripts differentially regulated between pretransplant biopsy samples and biopsies from patients with nephrotic syndrome. Candidate genes were screened by in situ hybridization for expression in the zebrafish pronephros, an easy-to-use in vivo assay system to assess podocyte function. One glomerulus-enriched product was the Rho-GTPase binding protein, IQGAP2. Immunohistochemistry found a strong presence of IQGAP2 in normal human and zebrafish podocytes. In zebrafish larvae, morpholino-based knockdown of iqgap2 caused a mild foot process effacement of zebrafish podocytes and a cystic dilation of the urinary space of Bowman's capsule upon onset of urinary filtration. Moreover, the glomerulus of zebrafish morphants showed a glomerular permeability for injected high-molecular-weight dextrans, indicating an impaired size selectivity of the glomerular filter. Thus, IQGAP2 is a Rho-GTPase binding protein, highly abundant in human and zebrafish podocytes, which controls normal podocyte structure and function as evidenced in the zebrafish pronephros.

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“…Moreover, Rigothier et al [32] reported that IQGAP1 regulates podocyte migration and permeability by interacting with components of the slit diaphragm complex. However, its role in podocyte apoptosis is still elusive.…”

Section: Discussionmentioning

confidence: 99%

IQGAP1 Mediates Angiotensin II-Induced Apoptosis of Podocytes via the ERK1/2 MAPK Signaling Pathway

et al. 2013

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Background/Aims: The mechanism underlying angiotensin II (AngII)-promoted podocyte apoptosis has not been established. IQ domain GTPase-activating protein 1 (IQGAP1) is a scaffolding protein of the mitogen-activated protein kinases (MAPK) signaling pathway, and plays a significant role in apoptosis. The present study evaluates the role of IQGAP1 in AngII-induced podocyte apoptosis. Methods: We randomly assigned 36 male Wistar rats to a normal saline-infused group, an AngII-infused group, or a normal control group, and measured podocyte apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and transmission electron microscopic analysis. In addition, we exposed differentiated mouse podocytes to AngII and then assessed apoptosis by flow cytometry and Hoechst-33258 staining. Expression of IQGAP1 was measured by Western blotting, real-time PCR and immunofluorescence assay in vivo and in vitro. IQGAP1 siRNA and MAPK pathway inhibitors were further introduced to investigate the role of IQGAP1 and MAPK signaling in the process. Coimmunoprecipitation was used to evaluate the interaction between ERK1/2 and IQGAP1. Results: AngII promoted podocyte apoptosis in vivo and in vitro. IQGAP1 had a linear distribution along the capillary loops of glomeruli in vivo, and was in the cellular membrane and cytoplasm of cultured podocytes. AngII stimulated IQGAP1 expression and increased phosphorylation of P38, JNK, and ERK1/2. Knockdown of IQGAP1 with siRNA prevented AngII-induced apoptosis of podocytes and reduced AngII-induced phosphorylation of ERK1/2, but not that of P38, JNK. This was accompanied by a reduced interaction between ERK1/2 and IQGAP1. Conclusion: IQGAP1 contributes to AngII-induced apoptosis of podocytes by interacting with the ERK1/2 signaling protein.

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IQGAP1 Interacts with Components of the Slit Diaphragm Complex in Podocytes and Is Involved in Podocyte Migration and Permeability In Vitro

Cited by 31 publications

References 45 publications

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

The Rho-GTPase binding protein IQGAP2 is required for the glomerular filtration barrier

IQGAP1 Mediates Angiotensin II-Induced Apoptosis of Podocytes via the ERK1/2 MAPK Signaling Pathway

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