Low-dose urapidil mitigates renal ischemia-reperfusion injury through matrix metalloproteinase-9 inhibition and anti-inflammatory effects

ObjectiveEvaluate a low-urapidil protocol (30 µg/kg bolus + 20 µg/kg/h infusion) on oxidative stress, inflammation, apoptosis, and matrix metalloproteinase-9 (MMP-9)-mediated matrix remodeling in a rat renal ischemia-reperfusion (I/R) injury model.Methods32 male Wistar rats were randomized into control (CR), sham (SH), I/R, and I/R + Urapidil (UR) groups. The CR group received no treatment, the SH group underwent laparotomy and intraperitoneal normal saline, the I/R group underwent laparotomy with 30-min of aortic clamping and 24 h of reperfusion, and the UR group received urapidil starting at 1 h before 30-min of aortic clamping (ischemia), followed by 24 h of reperfusion. Assessments included serum creatinine/urea, oxidative markers (total antioxidant status [TAS, total oxidant status [TOS]), inflammatory cytokines (tissue necrosis factor-alpha [TNF-α], interleukin [IL]-1β, IL-6, and MMP-9) via enzyme-linked immunosorbent assay, renal histopathology (hematoxylin and eosin staining), and immunohistochemistry (H-scores for endothelial nitric oxide synthase [eNOS], caspase-3, TNF-α, IL-1β, IL-6, and MMP-9).ResultsI/R significantly increased serum creatinine, urea, TNF-α, IL-1β, and TOS, and depleted TAS, indicating severe injury, oxidative stress, and inflammation. Extensive tubular necrosis, vacuolization, and edema were also observed. Immunohistochemistry revealed elevated levels of eNOS, caspase-3, cytokines, and MMP-9. Urapidil pretreatment effectively normalized serum creatinine/urea, restored TAS, reduced TOS and cytokines (TNF-α, IL-1β, IL-6) to baseline, and markedly alleviated histopathological damage. Urapidil significantly suppressed I/R-induced elevations in oxidative (eNOS), apoptotic (caspase-3), and inflammatory markers, and MMP-9 expression.ConclusionLow-dose urapidil confers significant protection against renal I/R injury by mitigating oxidative stress, inflammation, apoptosis, and MMP-9-mediated matrix degradation. The efficacy at microgram doses highlights its potential as a clinically relevant nephroprotective agent.