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Open AccessArticle

Angiotensin II-Induced Mesangial Cell Damage Is Preceded by Cell Membrane Permeabilization Due to Upregulation of Non-Selective Channels

1
Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda #340, 8331150 Santiago, Chile
2
Instituto Milenio, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, 2381850 Valparaíso, Chile
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(4), 957; https://doi.org/10.3390/ijms19040957
Received: 16 February 2018 / Revised: 20 March 2018 / Accepted: 20 March 2018 / Published: 23 March 2018
Connexin43 (Cx43), pannexin1 (Panx1) and P2X7 receptor (P2X7R) are expressed in kidneys and are known to constitute a feedforward mechanism leading to inflammation in other tissues. However, the possible functional relationship between these membrane channels and their role in damaged renal cells remain unknown. In the present work, we found that MES-13 cells, from a cell line derived from mesangial cells, stimulated with angiotensin II (AngII) developed oxidative stress (OS, thiobarbituric acid reactive species (TBARS) and generated pro-inflammatory cytokines (ELISA; IL-1β and TNF-α). The membrane permeability increased progressively several hours before the latter outcome, which was a response prevented by Losartan, indicating the involvement of AT1 receptors. Western blot analysis showed that the amount of phosphorylated MYPT (a substrate of RhoA/ROCK) and Cx43 increased progressively and in parallel in cells treated with AngII, a response followed by an increase in the amount in Panx1 and P2X7R. Greater membrane permeability was partially explained by opening of Cx43 hemichannels (Cx43 HCs) and Panx1 channels (Panx1 Chs), as well as P2X7Rs activation by extracellular ATP, which was presumably released via Cx HCs and Panx1 Chs. Additionally, inhibition of RhoA/ROCK blocked the progressive increase in membrane permeability, and the remaining response was explained by the other non-selective channels. The rise of activity in the RhoA/ROCK-dependent pathway, as well as in Cx HCs, P2X7R, and to a minor extent in Panx1 Chs led to higher amounts of TBARS and pro-inflammatory cytokines. We propose that AngII-induced mesangial cell damage could be effectively inhibited by concomitantly inhibiting the RhoA/ROCK-dependent pathway and one or more non-selective channel(s) activated through this pathway. View Full-Text
Keywords: connexin hemichannel; gap junction; P2X7 receptor; pannexin1 channel; extracellular ATP; oxidative stress; angiotensin receptors; Fasudil; Y-27632 connexin hemichannel; gap junction; P2X7 receptor; pannexin1 channel; extracellular ATP; oxidative stress; angiotensin receptors; Fasudil; Y-27632
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Gómez, G.I.; Fernández, P.; Velarde, V.; Sáez, J.C. Angiotensin II-Induced Mesangial Cell Damage Is Preceded by Cell Membrane Permeabilization Due to Upregulation of Non-Selective Channels. Int. J. Mol. Sci. 2018, 19, 957.

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