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Tetrandrine Suppresses Transient Receptor Potential Cation Channel Protein 6 Overexpression- Induced Podocyte Damage via Blockage of RhoA/ROCK1 Signaling

Authors Yu J, Zhu C, Yin J, Yu D, Wan F, Tang X, Jiang X

Received 11 October 2019

Accepted for publication 14 January 2020

Published 28 January 2020 Volume 2020:14 Pages 361—370

DOI https://doi.org/10.2147/DDDT.S234262

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Anastasios Lymperopoulos


Jin Yu, Caifeng Zhu, Jiazhen Yin, Dongrong Yu, Feng Wan, Xuanli Tang, Xue Jiang

Department of Nephrology, Guangxing Hospital Affiliated to ZheJiang Chinese Medical University (Key Laboratory of Zhejiang Province, Management of Kidney Disease), Hangzhou 310007, People’s Republic of China

Correspondence: Xue Jiang
Department of Nephrology, Guangxing Hospital Affiliated to ZheJiang Chinese Medical University (Key Laboratory of Zhejiang Province, Management of Kidney Disease), Hangzhou 310007, People’s Republic of China
Email monica_jiang@163.com

Objective: Podocyte damage is common in many renal diseases characterized by proteinuria. Transient receptor potential cation channel protein 6 (TRPC6) plays an important role in renal function through its regulation of intracellular Ca 2+ influx and RhoA/ROCK pathways. Chinese herb Stephania tetrandra, with the main active component being tetrandrine, has been used for the treatment of various kidney diseases for several years and has shown a positive effect. This study aimed at investigating the effect and mechanism of tetrandrine in podocyte damage induced by high expression of TRPC6.
Methods: Immortalized, differentiated murine podocytes, MPC5 were treated with valsartan (0– 800 μM) and tetrandrine (0– 40 μM) for 48 h. The maximum safe concentrations of valsartan and tetrandrine were selected using a cell viability assay. MPC5 podocytes stably expressing TRPC6 were constructed using a lentivirus packaging system, followed by treatment with valsartan, tetrandrine, and Y-27632 for 48 h and U73122 (10 μM) for 10 min. The RhoA/ROCK pathway and podocyte-specific proteins (nephrin and synaptopodin) levels were quantified. Podocyte apoptosis and intracellular Ca 2+ concentration were measured.
Results: Maximum safe concentrations of 100 μM valsartan and 10 μM tetrandrine showed no observable toxicity in podocytes. MPC5 podocytes stably expressing TRPC6 had higher intracellular Ca 2+ influx, apoptotic percentages, and expression of RhoA/ROCK proteins, but lower expression of nephrin and synaptopodin proteins. U73122 treatment for 10 min did not inhibit TRPC6, but suppressed RhoA/ROCK protein. Y-27632 decreased ROCK1 expression, but did not influence the expression of TRPC6 protein. Both 100 μM valsartan and 10 μM tetrandrine for 48 h significantly inhibited intracellular Ca 2+ influx, apoptosis, and RhoA/ROCK pathway, and increased nephrin and synaptopodin proteins in podocytes stably expressing TRPC6.
Conclusion: Elevated TRPC6 expression can lead to podocyte injury by inducing intracellular Ca 2+ influx and apoptosis of podocytes, and this effect may be mediated by activation of the RhoA/ROCK1 pathway. Tetrandrine can alleviate podocyte injury induced by TRPC6 expression through inhibition of the RhoA/ROCK pathway, suggesting a protective role in podocyte damage.

Keywords: tetrandrine, transient receptor potential cation channel protein 6, podocyte, RhoA/ROCK pathway

Corrigendum for this paper has been published

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