SMAD公司
Wnt信号通路
纤维化
纤维连接蛋白
上皮-间质转换
肾
细胞外基质
血尿素氮
医学
内科学
癌症研究
内分泌学
化学
信号转导
转化生长因子
生物化学
癌症
转移
作者
Jianfeng Zhang,Xiaocui Feng,Runling Yang,Jinhe Bai,Feiyun Gao,Bangzhi Zhang
标识
DOI:10.1124/jpet.123.001994
摘要
Renal fibrosis is distinguished by the abnormal deposition of extracellular matrix (ECM) and progressive loss of nephron function, with a lack of effective treatment options in clinical practice. In this study, we discovered that the Beclin-1-derived peptide MP1 significantly inhibits the abnormal expression of fibrosis and Epithelial-mesenchymal transition (EMT)-related markers, including α-Smooth muscle actin (α-SMA), Fibronectin (FN), Collagen I (Col I), Matrix metallopeptidase 2 (MMP2), Snail1, and Vimentin (Vim) both in vitro and in vivo. Hematoxylin-eosin (H&E) staining was employed to evaluate renal function, while serum creatinine (Scr) and blood urea nitrogen (BUN) were used as main indices to assess pathological changes in the obstructed kidney. The results demonstrated that daily treatment with MP1 during the 14-day experiment significantly alleviated renal dysfunction and changes in Scr and BUN in mice with unilateral ureteral obstruction (UUO). Mechanistic research revealed that MP1 was found to have a significant inhibitory effect on the expression of crucial components involved in both the Wnt/β-Catenin and TGF-β/Smad pathways, including β-Catenin, C-Myc, Cyclin D1, TGF-β1, and p-Smad/Smad. However, MP1 exhibited no significant impact on either the LC3II/LC3I ratio or P62 levels. These findings indicate that MP1 improves renal physiological function and mitigates the fibrosis progression by inhibiting the Wnt/β-Catenin pathway. Our study suggests that MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis. Significance Statement Our study indicated that the Beclin-1-derived peptide MP1 effectively mitigated renal fibrosis induced by UUO through inhibiting the Wnt/β-Catenin pathway and TGF-β/Smad pathway, thereby improving renal physiological function. Importantly, unlike other Beclin-1-derived peptides, MP1 exhibited no significant impact on autophagy in normal cells. MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis focusing on Beclin-1 derivatives and Wnt/β-Catenin pathway.
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