TβRI Independently Activates Smad- and CD2AP-Dependent Pathways in Podocytes

Xavier, Sandhya; Niranjan, Thiruvur; Krick, Stefanie; Zhang, Taoran; Ju, Wenjun; Shaw, Andréy S.; Schiffer, Mario; Böttinger, Erwin P.

doi:10.1681/asn.2008070806

Cited by 38 publications

(38 citation statements)

References 41 publications

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“…Lamouille et al (41) observed that translational regulation of epithelial-mesenchymal transition genes is mediated by TGF-␤-induced mTOR activation through PI3K and Akt. Akt is considered a prosurvival pathway, and TGF-␤1 is known to activate Akt through CD2AP in podocytes (52). Similar to the observation by Abe et al (53), we detected TSC2 phosphorylation at Thr 1462 .…”

Section: Volume 290 • Number 52 • December 25 2015supporting

confidence: 91%

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: Volume 290 • Number 52 • December 25 2015supporting

confidence: 91%

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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“…8B) (56,57,60,61). We also found that TGF-␤1 increased expression of ErbB4 and increased ErbB4 phosphorylation (Tyr-984), suggesting that it elicits intracellular signaling.…”

Section: Mir-146 In Podocytes and Diabetic Injurymentioning

confidence: 52%

Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1

Lee

Khan

Khaliqdina

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangPodocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. miR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a

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“…It can induce foot process effacement of podocytes and lead to cytoskeletal damage and abnormal molecular expression and distribution of podocytes. [6][7][8][9][10][11][12] In this study, we established podocyte injury models using Ang II in this part of the study by referring to the previous work of our group. 13,14 The experimental results demonstrated that the Ang II stimulation group showed foot process retraction at eight hours, and the cell area is reduced to 38.9% of the control group; the foot process significantly was reduced at 24 hours' stimulation, and the cell area declined to 5% of the control group; after stimulation for 48 hours, the cell area declined to 4.5% of the control group, and part of the podocytes showed foot process effacement and loss of intercellular junctions.…”

Section: Discussionmentioning

confidence: 99%

Influence of tacrolimus on podocyte injury inducted by angiotensin II

Hao

et al. 2015

J Renin Angiotensin Aldosterone Syst

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This study investigated the protective effect of FK506 in podocytes and the correlation of TRPC6 with podocyte injury repair. Methods: MPC5 were cultured in vitro, parallel with the control group, an Ang II stimulation group, and an FK506 intervention group. The apoptosis rate with flow cytometry also detected TRPC6 mRNA and protein expression by RT-PCR and Western blot, and then observed the distribution of TRPC6 with indirect immunofluorescence labeling under confocal microscope. Results: The activities of podocytes significantly increased after FK506 intervention for 24 hours and 48 hours when compared with the Ang II stimulation group, and the apoptosis rate was markedly lower than that of the Ang II stimulation group, while in contrast to TRPC6 mRNA and protein expression. Conclusion: FK506 can directly act on the podocytes to inhibit Ang II-induced damage on podocyte structures and reduce the apoptosis rate of podocytes, which may be related to stabilizing TRPC6 expression and distribution in podocytes by FK506, thus maintaining the structure and function integrity of the slit diaphragm and playing a role in protecting podocytes and antiproteinuria.

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TβRI Independently Activates Smad- and CD2AP-Dependent Pathways in Podocytes

Cited by 38 publications

References 41 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

Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1

Influence of tacrolimus on podocyte injury inducted by angiotensin II

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