Effects of vitexin on angiotensin II-induced kidney injury and its relationship with the AT1R/Smad3 pathway

Background: Angiotensin II (Ang II)-induced kidney injury is a critical pathway in the progression of chronic kidney disease, with the AT1R/Smad3 signaling axis playing a well-established role. The natural flavonoid vitexin has shown multi-organ protective effects, but its role and mechanism in Ang II-induced renal injury remain unclear. Objectives: To investigate the protective effect of vitexin against Ang II-induced kidney injury and explore whether its mechanism involves modulation of the AT1R/Smad3 pathway. Methods: In-vitro, Ang II-induced HK-2 cell injury models were treated with vitexin (20 ?mol/L) or valsartan (1 ?mol/L). Cell viability and SOD activity were assessed. Protein levels of AT1R, Smad2/3, p-Smad2/3, and Smad7 were detected by Western blotting. In-vivo, C57BL/6 mice with Ang II-induced kidney injury (1.1 mg/kg/d, 21 days) received vitexin (60 mg/kg, every other day) or vehicle. Blood pressure, urinary protein/creatinine ratio, renal histopathology (HE, PAS, Masson staining) and expression of AT1R/Smad3 pathway components were evaluated. Results: Vitexin significantly improved cell viability and SOD activity in HK-2 cells, comparable to valsartan. It downregulated AT1R, Smad2/3 and p-Smad2/3 while upregulating Smad7. In mice, vitexin lowered systolic blood pressure and the urinary protein/creatinine ratio, and alleviated renal histopathological damage, glomerular sclerosis, and fibrosis. It also reduced AT1R, p-Smad2/3, and CTGF expression and increased Smad7 in renal tissue. Conclusion: Vitexin attenuates Ang II-induced kidney injury by modulating the AT1R/Smad3 signaling pathway, suggesting its potential as a therapeutic candidate for renal injury. Further studies are needed to validate causal mechanisms and pharmacokinetics.