DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells

Abstract

The protective arm of the renin-angiotensin system (RAS), the ACE 2/Ang-(1–7)/MasR axis, has become a new anti-inflammatory target. As a specific activator of ACE2, diminazene aceturate (DA) can promote anti-inflammatory effects by regulating the ACE2/Ang-(1–7)/MasR axis. However, due to the reported toxicity of DA, its application has been limited. In the current study, we synthesized a low toxicity DA derivative 3 (DAD3) and sought to determine whether DAD3 can also activate ACE2 in bovine mammary epithelial cells (BMEC) and regulate the RAS system to inhibit inflammation. We found that both DA and DAD3 can activate and promote ACE2 expression in BMEC. iRNA-mediated knockdown of ACE2 demonstrated that DAD3 activates the ACE2/Ang-(1–7)/MasR axis and plays an anti-inflammatory role in BMEC. Furthermore, the inhibitory effects of DA and DAD3 on the protein phosphorylation of MAPK and NF-κB pathways were reduced in ACE2-silenced BMEC. Our findings show that ACE2 is a target of DAD3, which leads to inhibition of the MAPK and NF-κB signalling pathways and protects against LPS-induced inflammation in BMEC. Thus, DAD3 may provide a new strategy to treat dairy cow mastitis.

Overexpression of ACE2 ameliorates Aβ‐induced blood–brain barrier damage and angiogenesis by inhibiting NF‐κB/VEGF/VEGFR2 pathway

“…38 Studies have shown that overexpression or specific activation of ACE2 can counter the inflammatory response of LPS-induced epithelial cells by inhibiting the activation of the NF-κB pathway. 39,40 In our study, we showed that overexpression of ACE2 countered the activation of the NF-κB pathway caused by Aβ 25-35 , which not only inhibits the increased expression of VEGF but also may reduce…”

Dandelion root extracts and taraxasterol inhibit LPS‑induced colorectal cancer cell viability by blocking TLR4‑NFκB‑driven ACE2 and TMPRSS2 pathways

“…Second, TNFα, a downstream molecule of TLR4/NFκB, markedly increased the expression levels of ACE2 and TMPRSS2 at both the mRNA and protein levels. By contrast, Zhang et al (47) reported that high levels of ACE2 can protect against LPS-induced inflammation in bovine mammary epithelial cells by inhibiting the NFκB pathway. It has also been reported that LPS caused inflammatory damage in porcine intestinal epithelial cells (IPEC-J2) by inactivating ACE2 and stimulating pro-inflammatory cytokines (TNFα, IL1β and IL8), whereas knockdown of the ACE2 gene increased TLR4 expression and aggravated the inflammatory response (43).…”

Small Intestinal Endocrine Cell Derived Exosomal ACE2 Protects Islet β-Cell Function by Inhibiting the Activation of NLRP3 Inflammasome and Reducing β-Cell Pyroptosis

“…Notably, the diminished ACE2 expression disrupts the ACE2/Ang(1–7)/Mas pathway, subsequently attenuating its inhibitory effect on NFκB. 24 This culminates in heightened NFκB expression, thereby triggering the activation of NLRP3 inflammasomes and consequent cellular pyroptosis. 25 , 37 Existing studies have established a correlation between NLRP3 inflammasome activation and islets function, as well as the progression of diabetes.…”

“…22 The assembly of the NLRP3 inflammasome into a trimer, required for activation in response to endogenous danger signals, has been demonstrated in various studies. It is noteworthy that the activation of NFκB has been confirmed to initiate the assembly of the NLRP3 inflammasome, [23][24][25][26][27] and with the fact that the important relationship between ACE2, NFκB and the NLRP3 inflammasome is gradually revealed. [28][29][30][31] This also opens up new directions for exploring the regulatory initiation points, specific molecular pathways, and mechanisms behind the "gut-islets axis".…”