Acteoside alleviates UUO-induced inflammation and fibrosis by regulating the HMGN1/TLR4/TREM1 signaling pathway

Abstract

Purpose Acteoside (Act), a phenylethanoid compound that was first isolated from mullein, has been widely used for the investigation of anti-inflammatory and anti-fibrotic effect. However, the mechanism of Act against unilateral ureteral obstruction (UUO)-mediated renal injury is largely unknown. Therefore, this study aimed to explore the effects of Act on UUO rats and possible mechanisms. Methods A total of 20 Sprague-Dawley (SD) rats were divided randomly into three groups (n ≥ 6): (i) sham-operated group (Sham); (ii) UUO group (UUO+Saline); and (iii) UUO + Act 40 mg/kg/day, (UUO+Act); Continuous gavage administration for 2 weeks postoperatively, while the rats in Sham and UUO+saline groups were given equal amounts of saline. All rats were sacrificed after 14 days, the urine and blood samples were collected for biochemical analysis, the renal tissues were collected for pathological staining and immunohistochemistry. Correlations between individual proteins were analyzed by Pearson correlation analysis. Results The results of renal function indexes and histopathological staining showed that Act could improve renal function by reducing serum creatinine, blood urea nitrogen and urine protein at the same time, Act could alleviate renal inflammation and fibrosis. In addition, the results of immunohistochemistry showed that Act could reduce the expression of inflammation and kidney injury-related proteins F4/80, Mcp-1, KIM-1 proteins, as well as the expression of fibrosis-related protein α-SMA and β-catenin. More importantly, Act can also reduce the expression of HMGN1, TLR4 and TREM-1 proteins. Conclusion These data demonstrate that Act can ameliorate UUO-induced renal inflammation and fibrosis in rats probably through triggering HMGN1/TLR4/TREM-1 pathway.

Role of triggering receptor expressed on myeloid cells-1 in kidney diseases: A biomarker and potential therapeutic target

“…[102] After unilateral ureteral obstruction (UUO) in mice and rats, the expression of TREM-1 in the kidneys was upregulated. [48,[102][103][104] In a study, Tammaro et al [102] constructed a UUO model using TREM-1/3 KO mice and DPA12 KO mice, demonstrating that TREM-1 affects renal inflammation through the DAP12 pathway but does not affect fibrosis. A similar study showed that intraperitoneal injection of TREM-1-Fc had no significant effect on renal injury or fibrosis.…”

“…This suggests that the HMGN1 protein may activate the TREM-1 signaling pathway by triggering the TLR4 protein, leading to inflammation fibrosis development in the kidney. [104] It is well known that macrophages play an important role in fibrosis. Lo et al [48] found that the expression level of the M1 marker in the kidneys of TREM-1 KO mice was significantly lower than that of control mice, while the expression level of the M2 marker was the opposite.…”

Renal-Protective Roles of Lipoic Acid in Kidney Disease

“…The unilateral ureteral obstruction (UUO) animal model of kidney injury has been widely used to investigate the mechanisms of kidney injury and the therapeutic values of numerous agents [ 83 , 84 , 85 , 86 , 87 ]. This model has certain advantages in that it is a nonuremic normotensive disorder in the absence of any apparent inflammatory or toxic insult to the kidneys [ 88 ].…”

Lysine demethylase 5B transcriptionally regulates TREM1 in human cardiac fibroblasts

“…Previous reports have shown that TREM1 is upregulated in bleomycin-treated mouse alveolar epithelial cells, exerting pro-fibrotic effects in the lung by inducing cellular senescence [16]. Additionally, reducing TREM1 protein expression attenuates renal inflammation and fibrosis in rats subjected to unilateral ureteral obstruction [17]. The binding of soluble TREM1 to the membrane receptor ring guide receptor 2 activates downstream Smad2/3 and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathways, promoting hepatic stellate cell activation and liver fibrosis [18].…”