Salusin-α preserves glomerular endothelial barrier function in hypertension via YAP/ZO-1 signaling pathway

Abstract

Hypertensive nephropathy (HN) is a leading cause of end-stage renal disease, driven by glomerular endothelial barrier dysfunction, inflammation, and tight junction impairment. Salusin-α, an endogenous bioactive peptide with cardiovascular protective properties, has emerged as a potential regulator of renal homeostasis, but its role in hypertensive renal injury remains unclear. This study investigated the protective effects of Salusin-α on glomerular endothelial barrier function and its underlying mechanism via the YAP/ZO-1 signaling pathway. Male C57BL/6 mice were randomized into control, angiotensin II/high-salt (ANG/HS)-induced hypertensive, and ANG/HS + Salusin-α (1 or 2 μg/kg) groups. Hypertensive mice exhibited reduced serum and renal Salusin-α levels (∼43 % and ∼55 %, respectively), increased renal inflammation (IL-1β, TNF-α, MCP-1 upregulated 2.6–3.1-fold), albuminuria (82.6 vs. 19.3 μg/day in controls), and ZO-1 downregulation (∼51 %). Salusin-α treatment dose-dependently restored ZO-1 expression (95 % of control levels at 2 μg/kg) and reduced albuminuria (∼48 %). In human renal glomerular endothelial cells (HRGECs), Salusin-α (10 nM) mitigated ANG/HS-induced barrier dysfunction (FITC-dextran flux reduced from 41.3 % to 19.6 %; TEER restored from 105.2 to 169.8 Ω·cm²) by inhibiting YAP nuclear translocation (∼52 % reduction) and preserving ZO-1. Critically, YAP overexpression abolished Salusin-α’s protective effects on ZO-1 and barrier integrity. These findings demonstrate that Salusin-α alleviates hypertensive renal injury by suppressing YAP-mediated ZO-1 degradation, thereby preserving glomerular endothelial barrier function and reducing inflammation. The study identifies Salusin-α as a novel therapeutic candidate targeting the YAP/ZO-1 axis in hypertensive nephropathy.