肾脏纤维化的特点是细胞外基质(ECM)的异常沉积和肾单位功能的进行性丧失。在临床实践中缺乏有效的治疗选择。在这项研究中,我们发现Beclin-1衍生肽MP1显著抑制纤维化和上皮-间质转化(EMT)相关标志物的异常表达,包括α-平滑肌肌动蛋白(α-SMA),纤连蛋白(FN),胶原蛋白I(ColI),基质金属肽酶2(MMP2),Snail1和波形蛋白(Vim)在体外和体内。苏木精-伊红(H&E)染色用于评估肾功能,以血清肌酐(Scr)和血尿素氮(BUN)为主要指标来评估梗阻性肾脏的病理变化。结果表明,在14天的实验中,每天用MP1治疗可显着减轻单侧输尿管梗阻(UUO)小鼠的肾功能障碍以及Scr和BUN的变化。机制研究表明,MP1对Wnt/β-Catenin和TGF-β/Smad通路中关键成分的表达具有显著的抑制作用。包括β-连环蛋白,C-Myc,细胞周期蛋白D1、TGF-β1和p-Smad/Smad。然而,MP1对LC3II/LC3I比率或P62水平均无显著影响。这些发现表明MP1通过抑制Wnt/β-Catenin途径改善肾脏生理功能并减轻纤维化进展。我们的研究表明,MP1是治疗肾纤维化的一种有前途的新型候选药物前体。我们的研究表明,Beclin-1衍生肽MP1通过抑制Wnt/β-Catenin途径和TGF-β/Smad途径有效减轻UUO诱导的肾纤维化,从而改善肾脏生理功能。重要的是,与其他Beclin-1衍生肽不同,MP1对正常细胞自噬无明显影响。MP1代表了一种有前途的新型候选药物前体,用于治疗Beclin-1衍生物和Wnt/β-Catenin途径。
Renal fibrosis is distinguished by the abnormal deposition of extracellular matrix 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-related markers, including α-smooth muscle actin, fibronectin, collagen I, matrix metallopeptidase 2, Snail1, and vimentin both in vitro and in vivo. 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 pathologic 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. 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 transforming growth factor (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 physiologic 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: This study indicated that the Beclin-1-derived peptide MP1 effectively mitigated renal fibrosis induced by unilateral ureteral obstruction through inhibiting the Wnt/β-catenin pathway and transforming growth factor-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.