mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes

Vollenbröker, Beate; George, Britta; Wolfgart, Maria; Saleem, Moin A.; Pavenstädt, Hermann; Weide, Thomas

doi:10.1152/ajprenal.90319.2008

Cited by 105 publications

(106 citation statements)

References 45 publications

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“…has shown that phosphorylation of ERK1/2 regulates mTOR activation in different cell types (24,37,38). To elucidate the role of ERK1/2 in mTOR activation by TGF-␤1, ERK1/2 activation was inhibited by U0126 and PD184352, and 1 h of preincubation with these inhibitors significantly reduced mTOR and p70S6K phosphorylation by TGF-␤1 (Fig.…”

Section: Erk1/2 Regulates Tgf-␤1-induced Mtor Activation In a Tsc2-inmentioning

confidence: 91%

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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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Section: Erk1/2 Regulates Tgf-␤1-induced Mtor Activation In a Tsc2-inmentioning

confidence: 91%

“…Many growth factors, including insulin, insulin-like growth factor, and TGF-␤ and nutrients such as amino acids exert their cellular input through modulation of mTOR complexes (22,23). Akt, ERK1/2, and AMP-activated protein kinase are well known intermediate signaling molecules that transmit extracellular signals to mTOR (15,24).…”

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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“…32 Torras et al also reported that rapamycin provoked significant increase in proteinrua in PAN. 33 These contradictory results against our present data might be evoked by the difference of the start point to treat cells and animals with mTOR inhibitor although both previous papers did not describe its start point in detail.…”

Section: Mtorc1 and Upr In Podocyte N Ito Et Almentioning

confidence: 92%

mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome

Ito

Nishibori

Itô

et al. 2011

Laboratory Investigation

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Although podocyte damage is known to be responsible for the development of minimal-change disease (MCD), the underlying mechanism remains to be elucidated. Previously, using a rat MCD model, we showed that endoplasmic reticulum (ER) stress in the podocytes was associated with the heavy proteinuric state and another group reported that a mammalian target of rapamycin complex 1 (mTORC1) inhibitor protected against proteinuria. In this study, which utilized a rat MCD model, a combination of immunohistochemistry, dual immunofluorescence and confocal microscopy, western blot analysis, and quantitative real-time RT-PCR revealed co-activation of the unfolded protein response (UPR), which was induced by ER stress, and mTORC1 in glomerular podocytes before the onset of proteinuria and downregulation of nephrin at the post-translational level at the onset of proteinuria. Podocyte culture experiments revealed that mTORC1 activation preceded the UPR that was associated with a marked decrease in the energy charge. The mTORC1 inhibitor everolimus completely inhibited proteinuria through a reduction in both mTORC1 and UPR activity and preserved nephrin expression in the glomerular podocytes. In conclusion, mTORC1 activation may perturb the regulatory system of energy metabolism primarily by promoting energy consumption and inducing the UPR, which underlie proteinuria in MCD.

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“…3 In certain cell types, including the podocyte, chronic inhibition of MTOR by rapamycin also results in downregulation of mTORC2 functions. [4][5][6] Although this mechanism of action has not been completely elucidated, data in podocytes suggest that prolonged rapamycin treatment directly downregulates MTOR and Rictor, both of which are required for mTORC2 function. 6 Sirolimus (rapamycin) was originally proposed as an immunosuppressant to prevent rejection of solid organ transplants.…”

mentioning

confidence: 99%

Inhibition of MTOR Disrupts Autophagic Flux in Podocytes

Cinà

Onay

Paltoo

et al. 2012

Journal of the American Society of Nephrology

149

113

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Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubuleassociated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.

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mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes

Abstract: Vollenbröker B, George B, Wolfgart M, Saleem MA, Pavenstädt H, Weide T. mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes.

Cited by 105 publications

References 45 publications

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

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

mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome

Inhibition of MTOR Disrupts Autophagic Flux in Podocytes

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