Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

Chiluiza, David; Krishna, Sneha; Schumacher, Valérie; Schlöndorff, Johannes

doi:10.1074/jbc.m113.463059

Cited by 51 publications

(46 citation statements)

References 108 publications

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“…It has also been demonstrated that calpain 2 can be increased following Erk phosphorylation of serine 50. Further corroborating this possibility, recent evidence suggests that Erk phosphorylation is increased following glomerular injury (53). These results further emphasize the critical role of podocyte cell-matrix interactions in glomerular function in mice (2, 4), and humans (24,25) and how therapeutic targeting of these pathways may benefit patients (54).…”

Section: Discussionsupporting

confidence: 66%

Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance

Tian¹,

Kim²,

Monkley³

et al. 2014

J. Clin. Invest.

124

179

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Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between the podocyte and the glomerular basement membrane requires integrins, and defects in either α 3 or β 1 integrin, or the α 3 β 1 ligand laminin result in nephrotic syndrome in murine models. The large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to the actin cytoskeleton. Here, we found that mice lacking talin1 specifically in podocytes display severe proteinuria, foot process effacement, and kidney failure. Loss of talin1 in podocytes caused only a modest reduction in β 1 integrin activation, podocyte cell adhesion, and cell spreading; however, the actin cytoskeleton of podocytes was profoundly altered by the loss of talin1. Evaluation of murine models of glomerular injury and patients with nephrotic syndrome revealed that calpain-induced talin1 cleavage in podocytes might promote pathogenesis of nephrotic syndrome. Furthermore, pharmacologic inhibition of calpain activity following glomerular injury substantially reduced talin1 cleavage, albuminuria, and foot process effacement. Collectively, these findings indicate that podocyte talin1 is critical for maintaining the integrity of the glomerular filtration barrier and provide insight into the pathogenesis of nephrotic syndrome.

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Section: Discussionsupporting

confidence: 66%

Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance

Tian¹,

Kim²,

Monkley³

et al. 2014

J. Clin. Invest.

124

179

View full text Add to dashboard Cite

show abstract

“…Hence, despite similar overall levels of intracellular calcium upon complement stimulation in control and wtTRPC6 or dnTRPC6 overexpressing podocytes, local TRPC6-dependent differences in intracellular calcium levels that escape detection using whole-cell calcium measurement might control spatially confined regulatory pathways. The ERK pathway is activated in response to complement injury (39) and has been implicated in TRPC6 effects on podocytes (40). We found prominent ERK activation in response to complement, but this activation was not dependent on TRPC6 (Fig.…”

Section: The Protective Potential Of Trpc6 In Complement Injury To Pomentioning

confidence: 50%

Transient Receptor Potential Channel 6 (TRPC6) Protects Podocytes during Complement-mediated Glomerular Disease

Kistler

Singh

Altintas

et al. 2013

Journal of Biological Chemistry

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“…Recently, ERK signaling has been shown to be regulated downstream of TRPC6 [28,29,30]. Therefore, we examined whether TRPC6 mediates mesangial cell proliferation via ERK 1/2 in response to α 1 -AR stimulation.…”

Section: Resultsmentioning

confidence: 99%

Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells

Kong

Ma²,

Zou³

et al. 2015

Cell Physiol Biochem

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Background and Aims: There is accumulating evidence that sympathetic nervous hyperactivity contributes to the pathogenesis of glomerular sclerosis independent of blood pressure effects. A previous study showed that α₁-adrenoceptor (α₁-AR) antagonists inhibit mesangial cell (MC) proliferation. However, the underlying mechanism remains unclear. Methods and Results: We found that α₁-AR is expressed in a human mesangial cell line. The α₁-AR agonist phenylephrine (PE) induced Ca²⁺ influx as well as release from intracellular Ca²⁺ stores. Blockade of TRPC6 with siRNA, anti-TRPC6 antibodies and a TRPC blocker attenuated the PE-induced [Ca²⁺]_i increase. Additionally, the PE-induced [Ca²⁺]_i increase was phospholipase C dependent. Furthermore, PE induced a [Ca²⁺]_i increase even when the intracellular Ca²⁺ stores were already depleted. This effect was mimicked by an analog of diacylglycerol. These results suggested that, upon α₁-AR stimulation, TRPC6 mediates Ca²⁺ influx via a receptor-operated Ca²⁺ entry mechanism. Finally, TRPC6 contributes to the PE-induced MC proliferation. The mechanisms are associated with the extracellular signal-regulated kinase (ERK) signaling pathway because blockade of TRPC6 and chelation of extracellular Ca²⁺ abrogated PE-induced ERK1/2 abrogated PE-induced ERK1/2 phosphorylation. Conclusion: TRPC6 channels are involved in α₁-AR activation-induced Ca²⁺ entry, which mediates proliferation via ERK signaling in human MCs

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Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

Cited by 51 publications

References 108 publications

Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance

Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance

Transient Receptor Potential Channel 6 (TRPC6) Protects Podocytes during Complement-mediated Glomerular Disease

Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells

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