Potential crosstalk between the renin-angiotensin system and Neuropilin-1 pathways in experimental rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by persistent synovial inflammation, pathological angiogenesis, and progressive joint destruction. Emerging evidence implicates the renin-angiotensin system (RAS) and neuropilin-1 (NRP-1) as key modulators of RA pathogenesis through regulation of inflammatory signaling, vascular remodeling, and osteoclastogenesis. This study explored the mechanistic interplay between RAS and NRP-1 signaling in a rat model of RA induced by complete Freund's adjuvant. Experimental groups received valsartan (VAL), an angiotensin II type-1 receptor (AT-1R) antagonist; ramipril (RAM), an ACE inhibitor or methotrexate (MTX), the standard anti-rheumatic agent. NRP-1 ligand-binding (VEGF-165/Sema3A) and dimerization-associated domain expression were evaluated via immunohistochemistry and western blot. Transcriptional expression of VEGF-165, Sema3A was quantified using qRT-PCR, while RhoA, p-ERK protein levels were assessed by ELISA. Systemic inflammatory mediators (anti-CCP, TNF-α, IL-1β) and the bone resorption marker RANKL were also determined. Histopathological and scanning electron microscopy (SEM) analyses with morphometric evaluation assessed joint integrity. Both VAL and RAM significantly modulated NRP-1 signaling, influencing ligand-receptor interactions, dimerization, and downstream mediators (RhoA, p-ERK). These effects were accompanied by reduced inflammatory activity and preservation of bone and cartilage structure, suggesting that RAS blockade may confer chondroprotective and anti-inflammatory benefits via modulation of the NRP-1 axis. Collectively, the findings highlight a potential mechanistic cross-talk between RAS and NRP-1 pathways, offering a promising direction for future studies aimed at developing novel adjunctive strategies for RA management.