{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:29:09Z","timestamp":1760059749115,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2023-I2M-2-009"],"award-info":[{"award-number":["2023-I2M-2-009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013angiotensin 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&amp;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\/PPAR\u03b3 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\/PPAR\u03b3 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\/PPAR\u03b3 axis for the first time, which plays an important role in the progression of spontaneous hypertension combined with MAFLD.<\/jats:p>","DOI":"10.3390\/ijms26136541","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T10:03:27Z","timestamp":1751882607000},"page":"6541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Overexpression of (P)RR in SHR and Renin-Induced HepG2 Cells Leads to Spontaneous Hypertension Combined with Metabolic Dysfunction-Associated Fatty Liver Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Chen","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyi","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingzhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueman","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s00392-020-01709-7","article-title":"NAFLD and cardiovascular diseases: A clinical review","volume":"110","author":"Kasper","year":"2021","journal-title":"Clin. 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