Administration of Topical NorLeuAngiotensin(1-7) Minimizes Fibrotic Corneal Healing in Stellate Wound: A 28-Day Study.

Abstract

Severe full-thickness corneal lacerations disrupt the tight cellular and extracellular matrix (ECM) organization required for corneal transparency. Following injury, an influx of transforming growth factor beta (TGF&#x3b2;) into the corneal stroma signals the formation of haze-inducing myofibroblasts, resulting in excessive stromal remodeling and corneal haze. We hypothesized that MasR activation using NorLeuAngiotensin (1-7) (NLE) engages the pro-resolving arm of the renin-angiotensin system (RAS) to minimize fibrotic corneal repair. In this study, 6 mm stellate-shaped, full-thickness corneal lacerations were induced in New Zealand Black (NZB) rabbits and treated with topical vehicle, or 0.1%, 0.3%, or 0.45% NLE. Corneal healing was evaluated using noninvasive corneal imaging, histology, and the gene expression of RAS- and fibrosis-related targets (MasR, AT1R, TGF&#x3b2;R1). Corneal imaging revealed significantly decreased corneal haze (< 0.05) and increased keratocyte density with 0.1% NLE treatment (< 0.05). Immunofluorescence showed significantly reduced &#x3b1;-smooth muscle actin (&#x3b1;SMA), indicating decreased myofibroblast formation (< 0.05). Additionally, 0.1% NLE reduced stromal TGF&#x3b2;R1, suggesting that NLE mediates its activity by disrupting the TGF&#x3b2;/TGF&#x3b2;R axis. MasR and AT1R gene expression were downregulated, which contributes to a reduction in fibrosis. Collectively, these findings suggest that the NLE activation of MasR modulates RAS and TGF&#x3b2;/TGF&#x3b2;R signaling to reduce myofibroblast activity and fibrosis following severe corneal trauma.