Gao Chen, Guo Xinyi, Zhang Lingzhi, Lin Xueman, Sun Hua
State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Int J Mol Sci. 2025 Jul 7;26(13):6541. doi: 10.3390/ijms26136541.
Hypertension and metabolic dysfunction-associated fatty liver disease (MAFLD) are both common chronic diseases globally. Nearly half of patients with hypertension are complicated by MAFLD. The mechanisms of the bidirectional promotion between the two remain unclear. The (pro) renin receptor ((P)RR) is one of the classic members of the renin-angiotensin system (RAS) and serves as the receptor for prorenin. Although the role of (P)RR in the induction and progression of hypertension has been extensively studied, its role and underlying mechanisms in MAFLD remain underreported. In this study, we aim to investigate the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. In this study, SHRs were used for the model for hypertension combined with MAFLD. Liver lipid content analysis, liver H&E staining, the detection of (P)RR, ERK and downstream proteins related to fatty acid synthesis and transport, and RNA sequencing and data analysis were performed. In the in vitro experiments, we activated (P)RR using renin and established the lipid deposition model of HepG2 cells induced by renin for the first time. (P)RR was specifically blocked using handle region peptide (HRP), and Nile red fluorescence staining, (P)RR/ERK/PPARγ protein expression analysis, and immunofluorescence were performed to further verify the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. Our results demonstrate that (P)RR plays a role in the development and progression of hypertension combined with MAFLD. The hepatic TG and FFA levels in the SHRs were increased, and the protein expression of the (P)RR/ERK/PPARγ pathway and downstream proteins related to fatty acid synthesis and transport were upregulated. HRP reversed the activation of these proteins and reduced intracellular lipid accumulation. In conclusion, our study first reveals that (P)RR is a potential therapeutic target for hypertension combined with MAFLD. And we found the (P)RR/ERK/PPARγ axis for the first time, which plays an important role in the progression of spontaneous hypertension combined with MAFLD.
高血压和代谢功能障碍相关脂肪性肝病（MAFLD）都是全球常见的慢性疾病。近一半的高血压患者并发MAFLD。两者之间双向促进的机制仍不清楚。（前）肾素受体（(P)RR）是肾素 - 血管紧张素系统（RAS）的经典成员之一，作为肾素原的受体。尽管(P)RR在高血压的诱导和进展中的作用已得到广泛研究，但其在MAFLD中的作用和潜在机制仍报道较少。在本研究中，我们旨在探讨(P)RR在高血压合并MAFLD发病机制中的作用。在本研究中，使用自发性高血压大鼠（SHRs）建立高血压合并MAFLD模型。进行了肝脏脂质含量分析、肝脏苏木精 - 伊红（H&E）染色、(P)RR、细胞外信号调节激酶（ERK）以及与脂肪酸合成和转运相关的下游蛋白的检测，并进行了RNA测序和数据分析。在体外实验中，我们首次使用肾素激活(P)RR并建立了肾素诱导的HepG2细胞脂质沉积模型。使用柄区肽（HRP）特异性阻断(P)RR，并进行尼罗红荧光染色、(P)RR/ERK/过氧化物酶体增殖物激活受体γ（PPARγ）蛋白表达分析和免疫荧光，以进一步验证(P)RR在高血压合并MAFLD发病机制中的作用。我们的结果表明，(P)RR在高血压合并MAFLD的发生和发展中起作用。SHRs肝脏中的甘油三酯（TG）和游离脂肪酸（FFA）水平升高，(P)RR/ERK/PPARγ途径以及与脂肪酸合成和转运相关的下游蛋白的表达上调。HRP逆转了这些蛋白的激活并减少了细胞内脂质积累。总之，我们的研究首次揭示(P)RR是高血压合并MAFLD的潜在治疗靶点。并且我们首次发现了(P)RR/ERK/PPARγ轴，其在自发性高血压合并MAFLD的进展中起重要作用。
