Life · 2 authors, 3 centres
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High glucose exposure impairs retinal pigment epithelium (RPE) viability, tight junctions, and antioxidant activity while increasing inflammatory and angiogenic factors. Substance P (SP) treatment restored RPE cell viability, tight junction protein expression, and antioxidant function, and reduced ICAM-1, MCP-1, and VEGF levels via Akt signaling. These findings suggest SP as a potential therapeutic for diabetic retinopathy by protecting RPE barrier function and suppressing inflammation.
**Background:** Diabetic retinopathy (DR) is a microvascular complication of diabetes characterized by retinal edema and neovascularization, leading to vision loss. The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier (BRB) and is essential for photoreceptor health. High glucose (HG) disrupts RPE tight junctions, induces oxidative stress, and promotes inflammation and angiogenesis via factors like ICAM-1, MCP-1, and VEGF. Current treatments (e.g., anti-VEGF, steroids) have limitations. Substance P (SP), an endogenous neuropeptide, has shown protective effects in various cell types by modulating survival signaling and inflammation. This study investigated whether SP can protect RPE from HG-induced damage.
**Methods:** ARPE-19 cells were cultured in low glucose (LG, 1 g/L) or high glucose (HG, 4.5 g/L) medium for up to 48 hours. SP (100 nM) was added 24 hours after HG exposure. Cell viability was assessed by MTT assay, proliferation by population doubling time (PDT), and morphology by microscopy. Protein expression of tight junction proteins (ZO-1, E-cadherin), RPE65, ICAM-1, and Akt/phospho-Akt was measured by western blot. GPx activity was measured using a commercial kit. MCP-1 and VEGF secretion were quantified by ELISA. Monocyte migration was evaluated using a Transwell assay with THP-1 cells and RPE-conditioned medium.
**Key Results:** HG exposure for 24-48 h reduced RPE viability (76.18 ± 7.84% at 24 h; 71.1 ± 7.5% at 48 h) and proliferation (PDT: 42.5 ± 3.9 h vs. 31.2 ± 2.1 h in LG, p < 0.001). HG induced fibrotic morphology and decreased GPx activity (70.73 ± 2.43% at 24 h; 62.55 ± 4.51% at 48 h). HG reduced ZO-1 and E-cadherin expression at 24 and 48 h, and RPE65 expression at 48 h. ICAM-1 expression increased at 24 h and further at 48 h. MCP-1 and VEGF secretion were elevated at 24 and 48 h. SP treatment (24 h post-HG) improved cell viability (HG: 66.2 ± 5.4% vs. HG+SP: 80.48 ± 3.01%, p < 0.05) and restored GPx activity (HG: 58.3 ± 18.9% vs. HG+SP: 93.9 ± 11.7%). SP increased Akt phosphorylation within 10 min. SP preserved ZO-1, E-cadherin, and RPE65 expression, and reduced ICAM-1, MCP-1, and VEGF levels. Conditioned medium from SP-treated RPE decreased THP-1 monocyte migration compared to HG-treated RPE medium.
**Clinical Implications:** This in vitro study demonstrates that SP can counteract multiple HG-induced RPE dysfunctions, including oxidative stress, loss of barrier integrity, inflammation, and angiogenic factor production. By activating Akt signaling, SP enhances cell survival and antioxidant defenses. The reduction of ICAM-1, MCP-1, and VEGF suggests SP may suppress immune cell recruitment and neovascularization, key drivers of DR progression. SP's safety in non-clinical studies supports its potential as a novel therapeutic for DR. However, efficacy in animal models and clinical trials is needed before translation.