<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

Abstract

The role of angiotensin-converting enzyme 2 (ACE2) in silicosis remains unknown, although previous studies have suggested that ACE2 may be beneficial. We, therefore, investigated the effect of ACE2 on silicosis, particularly with regard to its role in regulating the epithelial-mesenchymal transition (EMT) induced by silica, with the aim to uncover a new potential target for the treatment of pulmonary fibrosis. Materials and Methods: We employed wild-type mice treated with diminazene aceturate (DIZE, an ACE2 activator, 15 mg/kg/day for 4 weeks), hACE2-transgenic mice (overexpress the ACE2 gene), and the mouse lung type II epithelial cell line treated with DIZE (10 −7 M for 48 h) or angiotensin-(1-7) [Ang-(1-7)] (10 −4 M for 48 h), following induced fibrotic responses to determine the protective potential of ACE2. Silicosis models were established by orotracheal instillation of SiO 2 (2.5 mg/mouse). Immunostaining was used to determine αsmooth muscle actin (α-SMA) expression. The activities of angiotensin-converting enzyme (ACE) and ACE2 and the levels of angiotensin II (Ang II) and Ang-(1-7) were detected by enzyme-linked immunosorbent assay. The mRNA expression of ACE and ACE2, and protein expression of the renin-angiotensin system (RAS) components and EMT indicators were studied by qRT-PCR and Western blot, respectively. Results: DIZE treatment and overexpression of ACE2 markedly inhibited the formation of silica-induced lung fibrosis and increased the level of E-cadherin, with concomitant downregulation of pro-collagen, vimentin, and α-SMA via RAS signaling. Furthermore, DIZE and Ang-(1-7) attenuated the EMT and collagen deposition induced by silica in MLE-12 cells. Moreover, these effects were abrogated by MLN-4760 (a specific ACE2 inhibitor) and A779 (a specific Mas receptor blocker). Conclusion: The overexpression of ACE2 and treatment with DIZE can ameliorate EMT in silicotic mice via activation of the ACE2-Ang-(1-7)-Mas receptor axis, and these changes are accompanied by suppression of the ACE-Ang II-AT1 receptor axis.

Thalidomide Alleviates Pulmonary Fibrosis Induced by Silica in Mice by Inhibiting ER Stress and the TLR4-NF-κB Pathway

“…It is well known that a drop in ACE level causes a drop in Ang II level. The renin–angiotensin–aldosterone system also plays an important role in the progression of silicosis fibrosis [ 43 ]; thus, the above research results support the results of this study, namely, treatment with thalidomide can inhibit the expression of TLR4. TLR4 is also crucial to the development of ER stress [ 44 , 45 ].…”

OC‐STAMP Overexpression Drives Lung Alveolar Epithelial Cell Type II Senescence in Silicosis

“…ER stress has been also observed in senescence induced by different stimuli and has been proposed as the consequence of senescent phenotype [ 24 ]. Combined with our previous study [ 1 , 25 ], we speculated that the EMT, ER stress, and cellular senescence worked together in silicosis, at least in part, by the overexpression of OC-STAMP.…”

Angiotensin II and Angiotensin Receptors 1 and 2—Multifunctional System in Cells Biology, What Do We Know?

“…Given the current epidemiological situation, the vast majority of scientific data are based on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) topic. Nevertheless, the role of RAS is not only based on the relationship with coronavirus disease 2019 (COVID-19), but also participates in the process of physiological functioning, proliferation, migration, and the overall process of oncogenesis [ 14 , 34 , 35 , 119 , 120 , 121 ]. The use of AT2R antagonists affects many aspects of neoplastic cells.…”

“…The role of the ACE/ACE2 balance is also not indifferent. ACE2 overexpression induced by diminazene aceturate (DIZE) lead to inhibition of the EMT induced by silica [ 14 ]. Interestingly, Ang 1-7 added together with Ang II diminished Ang II-induced changes in EMT markers expression [ 191 ].…”

“…Maintaining the appropriate proportions, in the context of activation of individual receptor subtypes, determines the proper functioning of cells. Consequently, any changes leading to a disturbance of proportions lead to pathological conditions [ 14 ].…”