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Author Notes:

Correspondence: Xuemei Zhang xuemzhang@fudan.edu.cn; Ker Yu keryu@fudan.edu.cn; Weiguang Zhang weiguangzhang1@163.com

These authors have contributed equally to this work: YW and JT

YW and JT designed the research, performed the part of experiments, interpreted the data, and performed the data analysis.

MW, FN, LY, XX, WZ, and HX performed the part of experiments.

HC, KY, and XZ interpreted the data, drafted the manuscript, and revised it critically for intellectual content.

All authors read and approved the final version of the manuscript before submission.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Research Funding:

This work was supported by grants from the National Science Foundation of China (Nos. 81773801 and 81573478 to XZ, No. 81603410 to JT), the fund of the State Key Laboratory of Kidney Diseases in PLA General Hospital (No. KF-01-124), Shanghai Science and Technology Innovation (No. 1414090 3202 to XZ), and the Department of Veteran Affairs MERIT Award 5I01BX000994 (HC).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Physiology
  • BK channels
  • mTORC2
  • Akt
  • SGK1
  • PKC alpha
  • podocyte
  • PROTEIN-KINASE-C
  • NF-KAPPA-B
  • BKCA CHANNELS
  • GLOMERULAR-FILTRATION
  • DIABETIC-NEPHROPATHY
  • EXPRESSION
  • RAPAMYCIN
  • CYTOSKELETON
  • ACTIVATION
  • SURFACE

Mechanism of Regulation of Big-Conductance Ca2+-Activated K+ Channels by mTOR Complex 2 in Podocytes

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Journal Title:

Frontiers in Physiology

Volume:

Volume 10

Publisher:

, Pages 167-167

Type of Work:

Article | Final Publisher PDF

Abstract:

Podocytes, dynamic polarized cells wrapped around glomerular capillaries, are an essential component of the glomerular filtration barrier. BK channels consist of one of the slit diaphragm (SD) proteins in podocytes, interact with the actin cytoskeleton, and play vital roles in glomerular filtration. Mechanistic target of rapamycin (mTOR) complexes regulate expression of SD proteins, as well as cytoskeleton structure, in podocytes. However, whether mTOR complexes regulate podocyte BK channels is still unclear. Here, we investigated the mechanism of mTOR complex regulation of BK channels via real-time PCR, western blot, immunofluorescence, and patch clamping. Inhibiting mTORC1 with rapamycin or downregulating Raptor had no significant effect on BK channel mRNA and protein levels and bioactivity. However, the dual inhibitor of mTORC1 and mTORC2 AZD8055 and short hairpin RNA targeting Rictor downregulated BK channel mRNA and protein levels and bioactivity. In addition, MK2206, GF109203X, and GSK650394, which are inhibitors of Akt, PKCα, and SGK1, respectively, were employed to test the downstream signaling pathway of mTORC2. MK2206 and GF109203X had no effect on BK channel protein levels. MK2206 caused an obvious decrease in the current density of the BK channels. Moreover, GSK650394 downregulated the BK channel protein and mRNA levels. These results indicate mTORC2 not only regulates the distribution of BK channels through Akt, but also modulates BK channel protein expression via SGK1 in podocytes.

Copyright information:

© 2019 Wang, Tao, Wang, Yang, Ning, Xin, Xu, Cai, Zhang, Yu and Zhang.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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