ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension

Abstract

The increase of Angiontesin-II (Ang-II), one of the key peptides of the renin-angiotensin system (RAS), and its binding to the Ang-II type 1 receptor (AT₁R) during hypertension is a crucial mechanism leading to AD\AM17 activation. Among the reported membrane anchored proteins cleaved by ADAM17, immunological cytokines (TNF-α, IFN-γ, TGF-β, IL-4, IL-10, IL-13, IL-6, FKN) are the major class of substrates, modulation of which triggers inflammation. The rise in ADAM17 levels has both central and peripheral implications in inflammation-mediated hypertension. This narrative review provides an overview of the role of ADAM17, with a special focus on its cellular regulation on neuronal and peripheral inflammation-mediated hypertension. Finally, it highlights the importance of ADAM17 with regards to the biology of inflammatory cytokines and their roles in hypertension.

Keywords: brain; inflammation; metalloprotease; periphery; renin-angiotensin system.

Figure 1

Role of ADAM17-mediated shedding on inflammatory cytokines and renin-angiotensin system (RAS) in hypertension. Angiotensin (Ang)-II is formed from the cleavage of Ang-I by angiotensin converting enzyme (ACE). Ang-II binds to Ang-II type 1 (AT₁R), and type 2 (AT₂R) receptors. Angiotensin converting enzyme type 2 (ACE2) acts on Ang-II and converts it into Ang-(1-7), which classically interacts with Mas receptor (MasR). Ang-(1-7) also can be produced by neprylisin (NEP) from Ang-I or from Ang-(1-9) through ACE. A desintegrin and metalloprotease 17 (ADAM17), a protease responsible for shedding membrane-anchored proteins, can be upregulated by Ang-II binding to AT₁R and downstream signaling pathways for instance ROS, PKC, MAPK, and Ca²⁺. In addition to ACE2 release from the cell surface, ADAM17 induces proinflammatory cytokines shedding such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and fractalkine (FKN). These cytokines stimulate the MAP kinase family as well as immune cells involved in the generation of central and periphery inflammation, which in turn, lead to hypertension. On the other hand, the figure shows a compensatory axis formed by Ang-II/AT₂R, ACE2/Ang-(1-7)/MasR and ALA/MrgD pathways that prevent the hypertension development. AD - aspartate decarboxylase, ALA – alamandine, MrgD – Mas-related G proteincoupled receptor member D.