Mammalian Target of Rapamycin Complex 2 Signaling Pathway Regulates Transient Receptor Potential Cation Channel 6 in Podocytes

Ding, Fangrui; Zhang, Xiaoyan; Li, Xuejuan; Zhang, Yanqin; Li, Baihong; Ding, Jie

doi:10.1371/journal.pone.0112972

Cited by 9 publications

(20 citation statements)

References 35 publications

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“…mTORC2 positively regulated TRPC6 in podocyte resulting in a massive calcium influx, which disrupted the filtration barrier, promoted the rearrangement of the highly dynamic podocyte actin cytoskeleton, and induced proteinuria. Inactivation of the Rictor/mTORC2 axis suppressed TRPC6 expression and decreased Ca + influx into the podocytes, thus reducing injury (14). In line with the latter observation, we demonstrated that HG/hyperglycemia is associated with activation of the Rictor/ mTORC2 signaling pathway and resulted in podocyte injury as assessed by a decrease in podocin expression and induction of podocyte loss/apoptosis.…”

Section: Fig 5 (Continued)supporting

confidence: 86%

“…MTORC2 SIGNALING IN DIABETIC NEPHROPATHYtransient receptor potential cation channel 6 (TRPC6) (14). mTORC2 positively regulated TRPC6 in podocyte resulting in a massive calcium influx, which disrupted the filtration barrier, promoted the rearrangement of the highly dynamic podocyte actin cytoskeleton, and induced proteinuria.…”

Section: Fig 5 (Continued)mentioning

confidence: 99%

“…Densitometric analysis was performed using NIH Image software (16-19, 21, 22). mRNA analysis mRNA was analyzed by real-time RT-PCR using the DDC t method (9)(10)(11)(12)(13)(14). Total RNA was isolated from cultured mouse podocytes or isolated glomeruli using the RNeasy Ò minikit (Qiagen, Valencia, CA).…”

Section: Western Blot Analysismentioning

confidence: 99%

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mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes

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Braych

et al. 2016

Antioxidants & Redox Signaling

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Aim: Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. We explored the hypothesis that mammalian target of rapamycin complex 2 (mTORC2) mediates podocyte injury in diabetes. Results: High glucose (HG)-induced podocyte injury reflected by alterations in the slit diaphragm protein podocin and podocyte depletion/apoptosis. This was paralleled by activation of the Rictor/mTORC2/Akt pathway. HG also increased the levels of Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using small interfering RNA (siRNA)-targeting Rictor in vitro decreased HG-induced Nox1 and Nox4, NADPH oxidase activity, restored podocin levels, and reduced podocyte depletion/apoptosis. Inhibition of mTORC2 had no effect on mammalian target of rapamycin complex 1 (mTORC1) activation, described by our group to be increased in diabetes, suggesting that the mTORC2 activation by HG could mediate podocyte injury independently of mTORC1. In isolated glomeruli of OVE26 mice, there was a similar activation of the Rictor/mTORC2/Akt signaling pathway with increase in Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using antisense oligonucleotides targeting Rictor restored podocin levels, reduced podocyte depletion/apoptosis, and attenuated glomerular injury and albuminuria. Innovation: Our data provide evidence for a novel function of mTORC2 in NADPH oxidasederived reactive oxygen species generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes. Conclusion: mTORC2 and/or NADPH oxidase inhibition may represent a therapeutic modality for diabetic kidney disease. Antioxid. Redox Signal. 25, 703-719.

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Section: Fig 5 (Continued)supporting

confidence: 86%

Section: Fig 5 (Continued)mentioning

confidence: 99%

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mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes

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Boutary

Braych

et al. 2016

Antioxidants & Redox Signaling

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“…The mTORC1 activation predominantly at Ser2448 leads to the phosphorylation of its downstream target p70S6K, while the mTORC2 activation predominantly at Ser2481 leads to the phosphorylation of Akt at Ser473 [14,17]. In ADR-treated podocytes, the phosphorylation of mTOR at Ser2481 increased significantly in a time-dependent manner, whereas the phosphorylation of mTOR at Ser2448 showed no change ( Fig.…”

Section: The Mtorc2 Activation Is Related To Adr-induced Podocyte Apomentioning

confidence: 89%

“…Recently, it was reported that the inhibition of mammalian target of rapamycin (mTOR), can regulate TRPC6 expression in cultured normal podocytes [14,15]. The serine/threonine kinase mTOR forms two distinct functional complexes, mTORC1 and mTORC2 [16].…”

Section: Introductionmentioning

confidence: 99%

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

Zhang

Wang

Ren

et al. 2016

Cell Physiol Biochem

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Background/Aims: Although increased expression and gain function of transient receptor potential cation channel 6 (TRPC6) has been associated with the pathogenesis of some proteinuric glomerular diseases, it remains elusive how TRPC6 participates in the process of podocyte damage. Methods: The potential signaling responsible for TRPC6 activation was investigated using immunoblot assays in an in vitro podocyte injury model induced by Adriamycin (ADR). Podocyte apoptosis was measured using FITC-conjugated Annexin V and Propidium Iodide staining. The channel activity of TRPC6 was assessed using the Ca²⁺ influx assay. Results: Increase of TRPC6 expression was detected in ADR-treated podocytes, and TRPC6 knockdown significantly decreased ADR-induced podocytes apoptosis. Following ADR treatment, phospho-mTOR^Ser2481 and phospho-Akt^Ser473 was significantly increased in a time-dependent manner, whereas phospho-mTOR^Ser2448 and phospho-p70S6K^Thr389 showed no change. ADR-induced apoptosis was prevented by ku0063794 (a dual mTOR complexes inhibitor), not by rapamycin (a specific mTORC1 inhibitor). Furthermore, nuclear translocation of NFκB/p65 was detected in ADR-treated podocytes, which was prevented by an Akt inhibitor triciribine. Of note, NFκB inhibitor PDTC prevented ADR-induced increase of TRPC6, and decreased ADR-induced apoptosis. We found that Akt activation and NFκB nuclear translocation was significantly inhibited by knockdown of mTORC2 protein Rictor, not by mTORC1 protein Raptor. In comparison with control, the Ca²⁺ influx was significantly increased in ADR-treated podocytes, which was remarkably prevented by TRPC6 knockdown. ADR-induced increase of TRPC6 channel activity was dramatically prevented by ku0063794, but not by rapamycin. Additionally, knockdown of Rictor, not Raptor, prevented ADR-induced increase of the Ca²⁺ influx. Moreover, the application of NFκB inhibitor PDTC also prevented the Ca²⁺ influx in ADR-treated podocytes. Conclusions: Our findings revealed that the mTORC2/Akt/NFκB pathway-mediated activation of TRPC6 participates in ADR-induced podocyte apoptosis.

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Cellular neurobiology of hyperforin

Bouron

2023

Phytotherapy Research

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Hyperforin is a phloroglucinol derivative isolated from the medicinal plant Hypericum perforatum (St John's wort, SJW). This lipophilic biomolecule displays antibacterial, pro‐apoptotic, antiproliferative, and anti‐inflammatory activities. In addition, in vitro and in vivo data showed that hyperforin is a promising molecule with potential applications in neurology and psychiatry. For instance, hyperforin possesses antidepressant properties, impairs the uptake of neurotransmitters, and stimulates the brain derived neurotrophic factor (BDNF)/TrkB neurotrophic signaling pathway, the adult hippocampal neurogenesis, and the brain homeostasis of zinc. In fact, hyperforin is a multi‐target biomolecule with a complex neuropharmacological profile. However, one prominent pharmacological feature of hyperforin is its ability to influence the homeostasis of cations such as Ca2+, Na+, Zn2+, and H+. So far, the pathophysiological relevance of these actions is currently unknown. The main objective of the present work is to provide an overview of the cellular neurobiology of hyperforin, with a special focus on its effects on neuronal membranes and the movement of cations.

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Mammalian Target of Rapamycin Complex 2 Signaling Pathway Regulates Transient Receptor Potential Cation Channel 6 in Podocytes

Cited by 9 publications

References 35 publications

mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes

mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes

The mTORC2/Akt/NFκB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis

Cellular neurobiology of hyperforin

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