Hypertensive Nephropathy: Unveiling the Possible Involvement of Hemichannels and Pannexons

Abstract

Hypertension is one of the most common risk factors for developing chronic cardiovascular diseases, including hypertensive nephropathy. Within the glomerulus, hypertension causes damage and activation of mesangial cells (MCs), eliciting the production of large amounts of vasoactive and proinflammatory agents. Accordingly, the activation of AT1 receptors by the vasoactive molecule angiotensin II (AngII) contributes to the pathogenesis of renal damage, which is mediated mostly by the dysfunction of intracellular Ca2+ ([Ca2+]i) signaling. Similarly, inflammation entails complex processes, where [Ca2+]i also play crucial roles. Deregulation of this second messenger increases cell damage and promotes fibrosis, reduces renal blood flow, and impairs the glomerular filtration barrier. In vertebrates, [Ca2+]i signaling depends, in part, on the activity of two families of large-pore channels: hemichannels and pannexons. Interestingly, the opening of these channels depends on [Ca2+]i signaling. In this review, we propose that the opening of channels formed by connexins and/or pannexins mediated by AngII induces the ATP release to the extracellular media, with the subsequent activation of purinergic receptors. This process could elicit Ca2+ overload and constitute a feed-forward mechanism, leading to kidney damage.

Activation of Pannexin-1 channels causes cell dysfunction and damage in mesangial cells derived from angiotensin II-exposed mice

“…Ang II-mediated activation of AT1 receptors is pivotal in the progressive deterioration of glomerular function, contributing to inflammatory and oxidative damage in renal diseases ( Rupérez et al, 2005 ; Lucero et al, 2022b ). Additionally, mesangial cells critically participate in glomerular hypertension and progressive renal disease ( da Silva Novaes et al, 2018 ; Zhao, 2019 ).…”

“…Like Panx1 channels, these channels facilitate communication between the cytoplasm and the extracellular environment, allowing the release of various molecules, including ATP. In hypertensive nephropathy, the elevated levels of Cx43 observed in the glomerulus and renal cortex emphasize its involvement in kidney injury ( Gómez et al, 2018 ; Lucero et al, 2022b ). Significantly, the ablation of Cx43 demonstrates a potential therapeutic avenue, improving renal function in chronic kidney disease induced by hypertension ( Haefliger et al, 2006 ; Alonso et al, 2010 ; Abed et al, 2014 ; Yang et al, 2014 ; Lucero et al, 2022a ).…”

Current perspectives and trends of the research on hypertensive nephropathy: a bibliometric analysis from 2000 to 2023

“…Naringenin has been found to retard the rise of Ang II levels and inhibit the increase of ACE/ACE2 and AT1R/AT2R protein ratio in mice models [ 60 ]. The opening of hemichannels and pannexons depended on intracellular Ca 2+ signaling, while the Ang II-mediated dysfunction of Ca 2+ signaling, led to renal damage [ 27 ]. Therefore, the hemichannels and pannexons may be novel targets in the treatment of Ang II-induced renal damage.…”

“…The heat shock protein (Hsp) 70 chaperone has been found to have cytoprotective effects on the Ang II-induced EMT after AT1R blockage [ 26 ]. Moreover, the hemichannels (HC) and pannexons, which are critical channels for intracellular Ca 2+ signaling, have been explored their roles in the Ang II-mediated renal damage [ 27 ]. Additionally, the abnormal activation of the complement system [ 28 ] and ferroptosis [ 29 ] also contributed to the pathogenesis of HTN.…”

Interaction of Angiotensin II AT1 Receptors with Purinergic P2X Receptors in Regulating Renal Afferent Arterioles in Angiotensin II-Dependent Hypertension

“…Connexin43 (Cx43) and Pannexin 1 (Panx1) channels have been extensively studied as crucial pathways for the production of ATP [44]. In cell lines derived from mesangial cells, Ang II stimulation increased a substrate of RhoA/ROCK and Cx43; this response was followed by an increase in Panx1 and P2X7R.…”