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.

Keywords: Ca2+ dynamics; connexin 43 hemichannel; gap junctions; hypertensive nephropathy; inflammation; oxidative stress; pannexins 1 channels.

Figure 1

Primary causes and morphological outcomes of chronic kidney disease. Although the leading causes of chronic kidney disease include diabetes and hypertension, other disorders such as glomerulonephritis, cystic kidney disease, and diverse urologic diseases also contribute in a minor proportion. Regardless of the etiology, the progressive reduction in glomerular filtration rate occurs accompanied by two common histological changes: glomerular sclerosis and tubular necrosis. Elaborated in BioRender.com (accessed on 15 October 2022).

Figure 2

Schematics showing general aspects of the generation of chronic kidney disease mediated by hypertensive nephropathy. At the renal level, arterial hypertension increases intra-glomerular pressure, leading to reductions in renal blood flow and alterations in the inflammatory profile of mesangial cells, podocytes, and epithelial cells. The epithelial cells boost the production of vasoactive and pro-inflammatory mediators, triggering a reduction in glomerular permeability and filtration. Consequently, hypertensive nephropathy can contribute to CKD. Renal impairment would then be associated mainly with the persistent production of AngII, which could augment the expression of proinflammatory cytokines [IL-1β and TNF-α] and the NOX-mediated generation of ROS. These processes likely result in macrophage infiltration and tubular overexpression of osteopontin, favoring the production of TGF- β1 and activation of NF-κB and AP-1. Elaborated in BioRender.com (accessed on 15 October 2022).

Figure 3

Structural organization of connexin and pannexin-based channels. Connexins and pannexins have four transmembrane domains (TM), two extracellular loops (EL), one cytoplasmatic loop (CL), and both the N- and C-terminus are localized on the intracellular side. The glycosylated extracellular loop of pannexins is also shown. Hemichannels or connexons are formed by the oligomerization of six subunits of connexins around a central pore, while pannexons are composed of seven pannexin subunits in the case of Panx1. Under normal conditions, the opening of hemichannels and pannexons is tightly regulated to fulfill several biological processes. Hemichannels and likely pannexons can also dock each other in junctional membrane interfaces to form cell-to-cell intercellular channels, termed gap junction channels. Elaborated in BioRender.com (accessed on 15 October 2022).

Figure 4

Schematic drawing of the localization of connexin and pannexin isoforms in the kidney. AA, afferent arteriole; EA, efferent arteriole; JGC, juxtaglomerular cells; Po, podocytes; Mes, mesangial cells; PT, proximal tubules; DLH, descending limb of loop of Henle; ALH, ascending limb of loop of Henle; DT, distal tubules; CT, collecting tubules; and Vr, Vasa recta. Elaborated in BioRender.com (accessed on 15 October 2022).

Figure 5

Scheme of possible signaling pathways involved in regulating of Cx43 hemichannels and Panx1 channels in mesangial cells stimulated with AngII. High AngII concentrations (10⁻⁷ M) activate angiotensin type 1 receptors (AT1R) in MCs, causing the PLC-mediated stimulation of IP3 receptors and further release of Ca²⁺ stored in the endoplasmic reticulum, NF-κB-dependent release of proinflammatory cytokines such as TNF-α and IL-1β, as well as the formation of reactive oxygen species (ROS). The resulting increase in [Ca²⁺]_i can also stimulate Panx1 channels and Cx43 hemichannels, eliciting the subsequent release of ATP to the extracellular compartment. Then, ATP activates P2X₇ and P2Y₁ receptors that, together with Cx43 hemichannels, permit a drastic increase in Ca²⁺ influx. As already seen in other systems, the increase in [Ca²⁺]_i promotes the expression and release of pro-inflammatory cytokines such as TNF-α, IL-1β via the activation of the inflammasome, and the generation of ROS. The release of ATP and influx of Ca²⁺ establish a positive feedback loop. Of note, alterations in [Ca²⁺]_i homeostasis mediated by Cx43 hemichannels or Panx1 channels could affect diverse aspects of MCs function (e.g., morphology and pro-inflammatory profile). Solid lines depict fluxes of molecules through channels, whereas dashed lines indicate activation or induction. Elaborated in BioRender.com (accessed on 15 October 2022).