Adenovirus-Mediated Gene Transfer of TGF-β1 to the Renal Glomeruli Leads to Proteinuria

Ghayur, Ayesha; Liu, Limin; Kolb, Martin; Chawla, Arun; Lambe, Shahid; Kapoor, Anil; Margetts, Peter J.

doi:10.1016/j.ajpath.2011.11.023

Cited by 22 publications

(19 citation statements)

References 54 publications

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“…In a recently described model of TGF-β overexpression in the glomerulus using an adenovirus [37], we found that ANGPT1 and ANGPT2 were both upregulated in the glomeruli from animals exposed to AdTGFB1, which is similar to observations by Campean et al [38] in the Thy 1.1 model of glomerular injury. In unstimulated podocytes, we found no expression of TEK, but exposure to TGF-β increased TEK expression.…”

Section: Communication Between Components Of the Filtration Barriersupporting

confidence: 89%

“…We were able to block the effects of TGF-β on podocytes in culture with small interfering RNA directed against TEK, or with antibodies directed against TEK or ANGPT1. We hypothesized that TGF-β is required for podocyte dedifferentiation either as a direct cofactor or through the induction of TEK receptors on podocytes [37].…”

Section: Communication Between Components Of the Filtration Barriermentioning

confidence: 99%

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Transforming growth factor-beta and the glomerular filtration barrier

Ghayur

Margetts

2013

Kidney Research and Clinical Practice

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The increasing burden of chronic kidney disease worldwide and recent advancements in the understanding of pathologic events leading to kidney injury have opened up new potential avenues for therapies to further diminish progression of kidney disease by targeting the glomerular filtration barrier and reducing proteinuria. The glomerular filtration barrier is affected by many different metabolic and immune-mediated injuries. Glomerular endothelial cells, the glomerular basement membrane, and podocytes—the three components of the filtration barrier—work together to prevent the loss of protein and at the same time allow passage of water and smaller molecules. Damage to any of the components of the filtration barrier can initiate proteinuria and renal fibrosis. Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine strongly associated with the fibrogenic response. It has a known role in tubulointerstitial fibrosis. In this review we will highlight what is known about TGF-β and how it interacts with the components of glomerular filtration barrier and causes loss of function and proteinuria.

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Section: Communication Between Components Of the Filtration Barriersupporting

confidence: 89%

Section: Communication Between Components Of the Filtration Barriermentioning

confidence: 99%

Transforming growth factor-beta and the glomerular filtration barrier

Ghayur

Margetts

2013

Kidney Research and Clinical Practice

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“…We chose recombinant adeno-associated virus (rAAV) to deliver shRNA against rat STIM1 to rat kidney, because the in vivo rAAV/shRNA delivery system has been well developed in rats. [51][52][53][54] The rAAV-carried eGFP-tagged shRNA against rat STIM1 (rAAV-eGFP-shStim1) was administered to rats by tail vein injection. An rAAV1/2 encoding an eGFP-tagged scrambled shRNA served as a control.…”

Section: In Vivo Knockdown Of Stim1 In Mcs Increased Col IV Protein Ementioning

confidence: 99%

Store–Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression

Wang

Davis

et al. 2015

Journal of the American Society of Nephrology

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Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca 2+ signals mediated by store-operated Ca 2+ channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca 2+ channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store-operated Ca 2+ channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium releaseactivated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II-induced fibronectin protein expression, whereas thapsigargin abrogated high glucose-and TGF-b1-stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno-associated virus-encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store-operated Ca 2+ channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.

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“…Furthermore, accumulation of TGF-␤ and its pathogenic roles in primary focal segmental glomerulosclerosis, progressive glomerulosclerosis, and diabetic nephropathy have been reported (26,28). In addition, adenovirus-mediated TGF-␤1 gene transfer to kidney glomeruli leads to proteinuria in rats (29). It has been reported recently that podocyte-specific overexpression of TGF-␤ induces segmental glomerulosclerosis with dysfunction in endothelial cells and podocyte depletion (30).…”

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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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Adenovirus-Mediated Gene Transfer of TGF-β1 to the Renal Glomeruli Leads to Proteinuria

Cited by 22 publications

References 54 publications

Transforming growth factor-beta and the glomerular filtration barrier

Transforming growth factor-beta and the glomerular filtration barrier

Store–Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression

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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