High glucose modifies transient receptor potential canonical type 6 channels via increased oxidative stress and syndecan-4 in human podocytes

Thilo, Florian; Lee, Marlene; Xia, Sheng-Yuan; Zakrzewicz, Andreas; Tepel, Martín

doi:10.1016/j.bbrc.2014.05.116

Cited by 25 publications

(18 citation statements)

References 25 publications

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“…This oxidative mode of TRPC6 regulation was originally described in heterologous expression systems [44] and it underlies mobilization of podocyte TRPC6 evoked by many different mediators, including insulin [13], Ang II [10,11], P2Y agonists such as ATP [12], elevated glucose [45] and even canonical lipid activators of TRPC6 such as diacylglycerol [14] and 20-HETE (unpublished observations). As a result of this process, oxidative stress in podocytes will inevitably be Sdc4 + C3T e) accompanied by sustained Ca 2+ influx which could over time contribute to podocyte detachment in an inflammatory milieu.…”

Section: Discussionmentioning

confidence: 92%

Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: An essential role for integrin signaling

Kim

Roshanravan

Dryer

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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PodocyteTRPC6 channels have been implicated in glomerular diseases. Syndecan-4 (Sdc4) is a membrane proteoglycan that can be cleaved to release a soluble ectodomain capable of paracrine and autocrine signaling. We have confirmed that overexpression of Sdc4 core protein increases surface abundance of TRPC6 channels in cultured podocytes, whereas Sdc4 knockdown has the opposite effect. Exposure to soluble Sdc4 ectodomain also increased the surface abundance of TRPC6, and increased cationic currents evoked by a diacylglycerol analog in podocytes. Sdc4 ectodomain increased generation of reactive oxygen species (ROS), reduced activation of RhoA, increased activation of Rac1, increased nuclear abundance of NFATc1, and increased total β3-integrin. The effects of Sdc4 ectodomain on cell-surface TRPC6 were blocked by the ROS quencher TEMPOL, and by the Rac1 inhibitor NSC-23766, but were not blocked by inhibition of calcineurin-NFATc1 signaling. The Sdc4 core protein co-immunoprecipitates with β3-integrin in cultured podocytes. Moreover, effects of Sdc4 ectodomain on TRPC6, ROS generation, Rac1 and RhoA modulation, and NFATc1 activation were blocked by cilengitide, a selective inhibitor of outside-in signaling through αv-containing integrins. Exposure to TNF, or serum from three patients with recurrent FSGS in relapse, increased shedding of podocyte Sdc4 ectodomains into the surrounding medium. This was also observed after treating podocytes with the metalloproteinase ADAM17 or after overexpression of the Sdc4 core protein. Increased concentrations of Sdc4 ectodomain were detected in urine of rats during acute puromycin aminonucleoside nephrosis. Locally generated Sdc4 may play a role in regulating TRPC6 channels, and may contribute to glomerular pathology.

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Section: Discussionmentioning

confidence: 92%

Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: An essential role for integrin signaling

Kim

Roshanravan

Dryer

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…In cultured human podocytes, Thilo et al recently found that highglucose treatment significantly increased TRPC6 expression at both mRNA and protein levels. These responses were blocked by tempol, a mimetic of superoxide dismutase, and mimicked by application of oxidative stress (201). Therefore, high glucose increased abundance of TRPC6 protein through ROS in podocytes.…”

Section: Fig 4 Diagram Depicting the Pathways Involved In Trpc6 Promentioning

confidence: 97%

“…For instance, ROS decreased abundance of TRPC6 protein in MCs (72, 122), but increased TRPC6 protein expression in podocytes (212,201,106). Although the mechanism for the celltype-specific effects of ROS is not known, one possibility is that ROS regulation of TRPC6 is cell context dependent.…”

Section: Discussionmentioning

confidence: 99%

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

Chaudhari

2016

Antioxidants & Redox Signaling

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Significance: Regulation of Ca 2+ signaling cascade by reactive oxygen species (ROS) is becoming increasingly evident and this regulation represents a key mechanism for control of many fundamental cellular functions. Canonical transient receptor potential (TRPC) 6, a member of Ca 2+ -conductive channel in the TRPC family, is widely expressed in kidney cells, including glomerular mesangial cells, podocytes, tubular epithelial cells, and vascular myocytes in renal microvasculature. Both overproduction of ROS and dysfunction of TRPC6 channel are involved in renal injury in animal models and human subjects. Although regulation of TRPC channel function by ROS has been well described in other tissues and cell types, such as vascular smooth muscle, this important cell regulatory mechanism has not been fully reviewed in kidney cells. Recent Advances: Accumulating evidence has shown that TRPC6 is a redox-sensitive channel, and modulation of TRPC6 Ca 2+ signaling by altering TRPC6 protein expression or TRPC6 channel activity in kidney cells is a downstream mechanism by which ROS induce renal damage. Critical Issues: This review highlights how recent studies analyzing function and expression of TRPC6 channels in the kidney and their response to ROS improve our mechanistic understanding of oxidative stress-related kidney diseases. Future Directions: Although it is evident that ROS regulate TRPC6-mediated Ca 2+ signaling in several types of kidney cells, further study is needed to identify the underlying molecular mechanism. We hope that the newly identified ROS/TRPC6 pathway will pave the way to new, promising therapeutic strategies to target kidney diseases such as diabetic nephropathy. Antioxid. Redox Signal. 25, 732-748.

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“…Possibilities for a direct/indirect TRPC channel activation via ROS are as follows: (1) activation of various intracellular proteins which can modulate TRPC function [187,203], (2) a direct activation of redox-sensitive TRP proteins that form hetero-multimeric channels with TRPC [212] and (3) activation of transcription factors, growth factors and cytokines that modulate TRPC expression [173] (Fig. 3).…”

Section: Redox Sensitivity Of Trpc Isoformsmentioning

confidence: 99%

“…For example, high glucose concentrations induced TRPC1/3/5/6 expression via elevation of ONOO − in human podocytes [173].…”

Section: Redox Sensitivity Of Trpc Isoformsmentioning

confidence: 99%

NADPH oxidases—do they play a role in TRPC regulation under hypoxia?

Malczyk

Veith

Schermuly

et al. 2015

Pflugers Arch - Eur J Physiol

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In the lung, acute alveolar hypoxia causes hypoxic pulmonary vasoconstriction (HPV) to maintain ventilation perfusion matching and thus optimal oxygenation of blood. In contrast, global chronic hypoxia triggers a pathological thickening of pulmonary arterial walls, called pulmonary vascular remodelling, leading to persistence of pulmonary hypertension (PH). Moreover, ischaemia or hypoxia can lead to a damage of pulmonary endothelial cells with subsequent oedema formation. Alterations in reactive oxygen species (ROS) have been suggested as a crucial mediator of such responses. Among the various sources of cellular ROS production, NADPH oxidases (NOXs) have been found to contribute to these physiological and pathophysiological signalling processes. NOXs are the only known examples that generate ROS as the primary function of the enzyme system. However, the downstream targets of NOX-derived ROS signalling in hypoxia are still not known. Canonical transient receptor potential (TRPC) channels recently have been recognised as directly or indirectly ROS-activated channels and have been shown to be essential for hypoxia-dependent vascular regulatory processes in the lung. Against this background, we here summarise the current knowledge on NOX-mediated TRPC channel signalling during hypoxia in the pulmonary circulation.

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High glucose modifies transient receptor potential canonical type 6 channels via increased oxidative stress and syndecan-4 in human podocytes

Cited by 25 publications

References 25 publications

Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: An essential role for integrin signaling

Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: An essential role for integrin signaling

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

NADPH oxidases—do they play a role in TRPC regulation under hypoxia?

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