Hypertensive Nephropathy: Unveiling the Possible Involvement of Hemichannels and Pannexons.

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.

TNF-α Plus IL-1ß Induces Opposite Regulation of Cx43 Hemichannels and Gap Junctions in Mesangial Cells through a RhoA/ROCK-Dependent Pathway.

Connexin 43 (Cx43) is expressed in kidney tissue where it forms hemichannels and gap junction channels. However, the possible functional relationship between these membrane channels and their role in damaged renal cells remains unknown. Here, analysis of ethidium uptake and thiobarbituric acid reactive species revealed that treatment with TNF-α plus IL-1ß increases Cx43 hemichannel activity and oxidative stress in MES-13 cells (a cell line derived from mesangial cells), and in primary mesangial cells. The latter was also accompanied by a reduction in gap junctional communication, whereas Western blotting assays showed a progressive increase in phosphorylated MYPT (a target of RhoA/ROCK) and Cx43 upon TNF-α/IL-1ß treatment. Additionally, inhibition of RhoA/ROCK strongly antagonized the TNF-α/IL-1ß-induced activation of Cx43 hemichannels and reduction in gap junctional coupling. We propose that activation of Cx43 hemichannels and inhibition of cell-cell coupling during pro-inflammatory conditions could contribute to oxidative stress and damage of mesangial cells via the RhoA/ROCK pathway.

Fenofibrate (a PPAR-α Agonist) Administered During Ethanol Withdrawal Reverts Ethanol-Induced Astrogliosis and Restores the Levels of Glutamate Transporter in Ethanol-Administered Adolescent Rats.

High-ethanol intake induces a neuroinflammatory response, which has been proposed as responsible for the maintenance of chronic ethanol consumption. Neuroinflammation decreases glutamate transporter (GLT-1) expression, increasing levels of glutamate that trigger dopamine release at the corticolimbic reward areas, driving long-term drinking behavior. The activation of peroxisome proliferator-activated receptor alpha (PPARα) by fibrates inhibits neuroinflammation, in models other than ethanol consumption. However, the effect of fibrates on ethanol-induced neuroinflammation has not yet been studied. We previously reported that the administration of fenofibrate to ethanol-drinking rats decreased ethanol consumption. Here, we studied whether fenofibrate effects are related to a decrease in ethanol-induced neuroinflammation and to the normalization of the levels of GLT-1. Rats were administered ethanol on alternate days for 4 weeks (2 g/kg/day). After ethanol withdrawal, fenofibrate was administered for 14 days (50 mg/kg/day) and the levels of glial fibrillary acidic protein (GFAP), phosphorylated NF-κB-inhibitory protein (pIκBα) and GLT-1, were quantified in the prefrontal cortex, hippocampus, and hypothalamus. Ethanol treatment increased the levels of GFAP in the hippocampus and hypothalamus, indicating a clear astrocytic activation. Similarly, ethanol increased the levels of pIκBα in the three areas. The administration of fenofibrate decreased the expression of GFAP and pIκBα in the three areas. These results indicate that fenofibrate reverts both astrogliosis and NF-κB activation. Finally, ethanol decreased GLT-1 expression in the prefrontal cortex and hippocampus. Fenofibrate normalized the levels of GLT-1 in both areas, suggesting that its effect in reducing ethanol consumption could be due to the normalization of glutamatergic tone.