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/jci12539

Cited by 227 publications

(159 citation statements)

References 45 publications

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Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

“…Podocalyxin functions also as anti-adhesin responsible for keeping the filtration slits open; it is associated with the actin cytoskeleton through the adaptor proteins Na + /H + Exchanger Regulatory Factor (NHERF)-1 and -2 [11] and ezrin [12]. Loss of glomerular foot process associates with uncoupling of podocalyxin from the actin cytoskeleton [11]. Another protein located on the apical cell membrane of foot process is the glomerular epithelial protein 1 ( GLEPP-1 ), a receptor tyrosine phosphatase involved in regulation of the podocyte cytoskeletal protein probably through direct or indirect interactions with vimentin [13].…”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

“…NPHS2 -null mice develop severe proteinuria during the antenatal period and die a few days after birth from renal failure [29]. Podocalyxin/NHERF2/ezrin/actin interactions are disrupted in pathologic conditions associated with changes in podocyte foot process, providing evidence of its relevance in vivo [11]. Furthermore, podocytes of podocalyxin-null mice exhibit profound defects in kidney development and die within 24 hours of birth with anuric renal failure [30].…”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

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Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

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Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

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Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

See 1 more Smart Citation

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

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“…How these processes are regulated at the ultrastructural level, however, has not been elucidated. To define the cytosolic components that link Podocalyxin to the cytoskeleton and regulate its activity as a blocker of adhesion, a number of groups have screened for intracellular Podocalyxin-binding proteins [13], [14], [15]. This led to the identification of the extremely versatile NHERF (Na+/H+ exchanger regulatory factor) family of adaptor proteins (reviewed in [16], [17]) as Podocalyxin binding partners.…”

Section: Introductionmentioning

confidence: 99%

The CD34-Related Molecule Podocalyxin Is a Potent Inducer of Microvillus Formation

et al. 2007

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BackgroundPodocalyxin is a CD34-related transmembrane protein involved in hematopoietic cell homing, kidney morphogenesis, breast cancer progression, and epithelial cell polarization. Although this sialomucin has been shown to block cell adhesion, the mechanisms involved remain enigmatic. It has, however, been postulated that the adaptor proteins NHERF-1 and 2 could regulate apical targeting of Podocalyxin by linking it to the actin cytoskeleton.Principal FindingsHere, in contrast, we find that full-length Podocalyxin acts to recruit NHERF-1 to the apical domain. Moreover, we show that ectopic expression of Podocalyxin in epithelial cells leads to microvillus formation along an expanded apical domain that extends laterally to the junctional complexes. Removal of the C-terminal PDZ-binding domain of Podocalyxin abolishes NHERF-1 recruitment but, surprisingly, has no effect on the formation of microvilli. Instead, we find that the extracellular domain and transmembrane region of Podocalyxin are sufficient to direct recruitment of filamentous actin and ezrin to the plasma membrane and induce microvillus formation.Conclusions/SignificanceOur data suggest that this single molecule can modulate NHERF localization and, independently, act as a key orchestrator of apical cell morphology, thereby lending mechanistic insights into its multiple roles as a polarity regulator, tumor progression marker, and anti-adhesin.

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“…This actin network enables the podocytes to perform a host of biological functions, including motility and maintaining the permeability barrier "slit diaphragm." Study of various glomerular disease models shows a severely disorganized actin network that is associated with loss of podocyte function and alterations in the podocyte morphology, a process commonly known as podocyte effacement (5)(6)(7). Podocyte effacement and the loss of slit diaphragm have been the subjects of intense investigation in recent years, which has led to the identification of several proteins that play a role in maintaining podocyte structure and function (1,8).…”

mentioning

confidence: 99%

Structural Analysis of the Myo1c and Neph1 Complex Provides Insight into the Intracellular Movement of Neph1

Arif

Sharma

Solanki

et al. 2016

Molecular and Cellular Biology

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The Myo1c motor functions as a cargo transporter supporting various cellular events, including vesicular trafficking, cell migration, and stereociliary movements of hair cells. Although its partial crystal structures were recently described, the structural details of its interaction with cargo proteins remain unknown. This study presents the first structural demonstration of a cargo protein, Neph1, attached to Myo1c, providing novel insights into the role of Myo1c

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

Cited by 227 publications

References 45 publications

Podocyte Mitosis – A Catastrophe

Podocyte Mitosis – A Catastrophe

The CD34-Related Molecule Podocalyxin Is a Potent Inducer of Microvillus Formation

Structural Analysis of the Myo1c and Neph1 Complex Provides Insight into the Intracellular Movement of Neph1

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