The podocyte's response to stress: the enigma of foot process effacement

Kriz, Wilhelm; Shirato, Isao; Nagata, Michio; LeHir, Michel; Lemley, Kevin V.

doi:10.1152/ajprenal.00478.2012

Cited by 247 publications

(268 citation statements)

References 95 publications

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“…A previous study showed that signals between slit diaphragm proteins have an important role in the regulation of podocyte function, survival, and actin remodeling (3). Morphological changes in the foot processes of podocytes have been correlated with changes in podocyte cell bodpodocytes with pseudocysts which was found by using TEM and SEM in previous studies (14)(15)(16)25), our results support the idea that damaged podocytes undergo cell-body morphological changes. The present results on podocyte alterations observed by LVSEM are also similar to the findings of previous reports.…”

Section: Discussionsupporting

confidence: 90%

A novel approach to the histological diagnosis of pediatric nephrotic syndrome by low vacuum scanning electron microscopy

et al. 2014

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Despite intensive treatment, steroid-resistant nephrotic syndrome (NS) often progresses to endstage renal disease. Therefore, a more accurate and quick histological diagnosis is required to properly treat such patients. The aim of this study was to introduce a novel approach to the histological diagnosis of pediatric NS by low vacuum scanning electron microscopy (LVSEM) and to describe the morphological differences in glomeruli between steroid-sensitive and steroid-resistant NS specimens. The subjects were three patients with steroid-sensitive NS and four patients with steroid-resistant NS. Conventional renal biopsy paraffin sections were stained with platinum-blue (Pt-blue) or periodic acid methenamine silver (PAM) and directly observed under LVSEM at magnifications between ×50 and ×10,000. The Pt-blue-stained sections showed three-dimensional structural alterations in glomerular podocytes and foot processes. PAM-stained sections showed changes in the structure and thickness of the glomerular basement membrane (GBM). Consequently, many round-shaped podocytes and elongated primary foot processes were exclusively recognized in steroid-resistant NS, although irregularities in foot process interdigitation, fusions, effacements, and microvillus transformations were observed in both steroid-sensitive and steroidresistant NS. Irregularities in thickness and the wrinkling of GBMs were clearly detected in steroid-resistant NS. The evaluation by LVSEM is probably useful for the renal histological diagnosis of pediatric NS.Nephrotic syndrome (NS) comprises proteinuria, hypoalbuminemia, hypercholesterolemia, and edema. Pediatric patients with NS are usually treated with corticosteroids (13). Patients who respond to steroids (steroid-sensitive NS) have good clinical outcomes, whereas patients who do not respond to steroids (steroid-resistant NS) are predisposed to the development of end-stage renal disease. Histopathologically, most pediatric patients with steroid-sensitive NS show minor glomerular abnormalities, and patients with steroid-resistant NS generally have focal segmental glomerulosclerosis (FSGS) (25). Under light microscopy (LM), minor glomerular abnormalities are defined as a slight or no increase in the mesangial matrix or cellularity without focal segmental glomerular collapse, scarring, endocapillary proliferation, or adhesions. FSGS shows focal and segmental glomerular collapse, scarring, endocapillary proliferation, or adhesions of glomeruli with minimal abnormalities (21). However, it is not clear whether the glomeruli with no obvious changes in FSGS are different from those in minor glomerular abnormalities. In addition, it is difficult to diagnose FSGS when the NS biopsy section does not include glomeruli with the typical alterations of FSGS described above, although the differential diagnosis between minor glomerular abnormalities and FSGS is very

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Section: Discussionsupporting

confidence: 90%

A novel approach to the histological diagnosis of pediatric nephrotic syndrome by low vacuum scanning electron microscopy

et al. 2014

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“…Adhesion to the glomerular basement membrane (GBM) is a prerequisite of healthy podocytes; detachment from the GBM and loss of podocytes in the urine is a common finding in glomerular diseases. [7][8][9] Despite a growing interest in potential therapeutic strategies to avoid podocyte detachment, there is incomplete knowledge of the dynamic mechanisms that regulate the anchorage of podocyte ramifications to the GBM 7,8,[10][11][12] in order to maintain physiological properties and counteract the continuous mechanical stress due to the high transcapillary filtration pressure. 13 The use of biomaterials offers a unique method to produce surfaces with different nanotopographies and those best fitting cell-specific requirements.…”

Section: Introductionmentioning

confidence: 99%

A nanoporous surface is essential for glomerular podocyte differentiation in three-dimensional culture

Zennaro¹,

Rastaldi²,

Bakeine³

et al. 2016

IJN

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Although it is well recognized that cell–matrix interactions are based on both molecular and geometrical characteristics, the relationship between specific cell types and the three-dimensional morphology of the surface to which they are attached is poorly understood. This is particularly true for glomerular podocytes – the gatekeepers of glomerular filtration – which completely enwrap the glomerular basement membrane with their primary and secondary ramifications. Nanotechnologies produce biocompatible materials which offer the possibility to build substrates which differ only by topology in order to mimic the spatial organization of diverse basement membranes. With this in mind, we produced and utilized rough and porous surfaces obtained from silicon to analyze the behavior of two diverse ramified cells: glomerular podocytes and a neuronal cell line used as a control. Proper differentiation and development of ramifications of both cell types was largely influenced by topographical characteristics. Confirming previous data, the neuronal cell line acquired features of maturation on rough nanosurfaces. In contrast, podocytes developed and matured preferentially on nanoporous surfaces provided with grooves, as shown by the organization of the actin cytoskeleton stress fibers and the proper development of vinculin-positive focal adhesions. On the basis of these findings, we suggest that in vitro studies regarding podocyte attachment to the glomerular basement membrane should take into account the geometrical properties of the surface on which the tests are conducted because physiological cellular activity depends on the three-dimensional microenvironment.

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“…Leakage of plasma proteins in the urine indicates the onset of renal diseases that are associated with podocyte injury (2)(3)(4). Recent evidence has shown that mammalian target of rapamycin (mTOR) 3 signaling activation is an important mediator of diabetic nephropathy in mice and humans (5,6).…”

mentioning

confidence: 99%

Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis

Das

Nguyen

et al. 2015

Journal of Biological Chemistry

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TGF-␤ is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-␤1 induces the selective up-regulation of mitochondrial Nox4, playing critical roles in podocyte apoptosis. Here we investigated the regulatory mechanism of Nox4 up-regulation by mTORC1 activation on TGF-␤1-induced apoptosis in immortalized podocytes. TGF-␤1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-␤ receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTOR⌬ augmented TGF-␤1-treated Nox4 expression, reactive oxygen species (ROS) generation, and apoptosis, whereas mTOR kinase-dead suppressed the above changes. In addition, knockdown of mTOR mimicked the effect of mTOR-KD. Inhibition of mTORC1 by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-␤1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-␤1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-␤1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-␤1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-␤1-induced ERK1/2-mTOR activation. Our data suggest that TGF-␤1 increases translation ofNox4throughtheSmad-ERK1/2-mTORC1axis,whichisindependent of transcriptional regulation. Activation of this pathway plays a crucial role in ROS generation and mitochondrial dysfunction, leading to podocyte apoptosis. Therefore, inhibition of the ERK1/2-mTORC1 pathway could be a potential therapeutic and preventive target in proteinuric and chronic kidney diseases.Podocyte damage is one of the key determinants of the majority of diabetic and non-diabetic glomerular diseases, leading to chronic kidney diseases and end-stage renal disease (1). Leakage of plasma proteins in the urine indicates the onset of renal diseases that are associated with podocyte injury (2-4). Recent evidence has shown that mammalian target of rapamycin (mTOR) 3 signaling activation is an important mediator of diabetic nephropathy in mice and humans (5, 6). Increased mTOR activity has been reported in different glomerular diseases, and mTORC1 inhibition by rapamycin and everolimus shows beneficial effects against diabetic nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, etc. (7-10). But contrasting evidence also indicates that mTORC1 inhibition by the immunosuppressive drug rapamycin leads proteinuria and podocyte apoptosis and develops primary focal segmental glomerulosclerosis in renal transplant recipients (11). Therefore, it might be important to investigate the detailed molecular mechanisms to...

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The podocyte's response to stress: the enigma of foot process effacement

Cited by 247 publications

References 95 publications

A novel approach to the histological diagnosis of pediatric nephrotic syndrome by low vacuum scanning electron microscopy

A novel approach to the histological diagnosis of pediatric nephrotic syndrome by low vacuum scanning electron microscopy

A nanoporous surface is essential for glomerular podocyte differentiation in three-dimensional culture

Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis

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