Sulfonation modification of peptides and their protective effect on angiotensin II-induced HK-2 cell injury

The biological properties of peptides are determined by their amino acid sequences, but the diversity of naturally occurring amino acids is limited. Accordingly, this study aimed to investigate the impact of sulfonation modification on the functional characteristics of peptide LALFVPR (LR-7), such as water solubility, stability, and antioxidant, anti-inflammatory, and angiotensin-converting enzyme (ACE) inhibitory activity. The results showed that the sulfonated peptide LC(SO₃)LFVPR (LR-7S) exhibited significantly improved water solubility (a 46-fold increase) and greater stability in gastric fluid compared to LR-7. In HK-2 cells exposed to 5 μM angiotensin II (Ang II) for 24 h, treatment with 100 μM LR-7S more effectively mitigated cellular damage, as indicated by enhanced mitochondrial membrane potential and increased cell viability. Notably, LR-7S treatment resulted in lower reactive oxygen species (ROS) levels and higher activities of catalase (CAT) and superoxide dismutase (SOD) relative to LR-7. This antioxidant effect may be associated with the promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Both LR-7 and LR-7S significantly decreased the levels of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and nuclear factor kappa-B (NF-κB). Furthermore, LR-7S exhibited a lower binding energy (-6.16 kcal mol^-1) with ACE and its ACE inhibitory activity was 162% higher than that of LR-7 at a concentration of 25 μM. These findings highlight sulfonation as an effective strategy for modulating the peptide structure and enhancing bioactivity. Despite the challenges in clarifying the metabolic pathways <i>in vivo</i>, the sulfonated peptide holds great promise for the development of the management of hypertensive nephropathy.