PRR promotes hypertensive renal injury by activating Wnt/β-catenin signaling and inflammation infiltration in mice

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2025-01, Vol.1871 (1), p.167517, Article 167517
• Main Authors: Lin, Mengjiao, Wang, Dedong, Chen, Yanlan, Chen, Gewenhan, Zhou, Yanni, Ou, Juanjuan, Xiao, Liangxiang
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; beta Catenin - genetics; beta Catenin - metabolism; Fibrosis; Humans; Hypertension - metabolism; Hypertension - pathology; Hypertension nephropathy; Hypertension, Renal - metabolism; Hypertension, Renal - pathology; Inflammation; Inflammation - metabolism; Inflammation - pathology; Kidney - metabolism; Kidney - pathology; Male; Mice; Mice, Inbred C57BL; Nephritis - metabolism; Nephritis - pathology; Prorenin Receptor; PRR; RAS; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Renin-Angiotensin System; Wnt Signaling Pathway; Wnt/β-catenin
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167517

Hypertension stands out as a substantial independent risk factor in the progression of chronic kidney disease; however, the exact pathological mechanisms remain elusive. Our preliminary studies find that Wnt/β-catenin control renin-angiotensin system (RAS) expression, thus playing an important role in the pathogenesis of hypertension and renal fibrosis. As an integral component of the RAS, the (pro)renin receptor (PRR) plays a crucial role in the activation of the RAS and hypertension. Recent studies suggest a reciprocal relationship between PRR and Wnt/β-catenin signaling, potentially contributing to hypertensive renal fibrosis development. To assess the role of PRR in mediating hypertensive nephropathy, we manipulated this signaling by over expression of PRR ligand or blockade of PRR by siPRR. In vivo, PRR induction promoted hypertension, proteinuria, renal fibrosis, inflammatory response and β-catenin activation in Ang II induced hypertension mice. Conversely, blockade of PRR inhibited Ang II mediated hypertension, renal fibrosis and inflammation. In vitro, PRR over expression renal tubular cells exacerbated the Ang II induced fibrotic response and inflammation. Moreover, PRR was upregulated in hypertensive nephropathy patients, and correlated with renal function and renal fibrosis. These results indicate that PRR interact with Wnt/β-catenin signaling promote the progression of hypertensive nephropathy. PRR could be served as a biomarker for the diagnosis and treatment of hypertensive renal fibrosis. •PRR and Hypertensive Nephropathy: This study elucidates the role of the (pro)renin receptor (PRR) in hypertensive nephropathy, highlighting its involvement in the progression of renal fibrosis and hypertension.•Mechanistic Insights: The research identifies a positive feedback loop between PRR and the Wnt/β-catenin signaling pathway, which exacerbates renal fibrosis and inflammation in hypertensive nephropathy.•In Vivo and In Vitro Evidence: PRR overexpression was shown to aggravate renal damage and proteinuria in hypertensive mice, while PRR downregulation alleviated these effects. In vitro studies corroborated these findings, demonstrating enhanced fibrotic responses in renal tubular cells with PRR overexpression.•Clinical Relevance: PRR expression was significantly elevated in renal tissue from hypertensive nephropathy patients compared to controls, correlating with renal dysfunction and fibrosis. This suggests PRR as a potential biomarker for assessing