Knockdown of Leucine-rich alpha-2-glycoprotein 1 alleviates renal ischemia-reperfusion injury by inhibiting NOX4-mediated apoptosis, inflammation, and oxidative stress

Abstract

Renal ischemia-reperfusion (I/R) injury leads mainly to acute kidney injury. Leucine-rich alpha-2-glycoprotein 1 (LRG) is upregulated in kidney tissues of mice after renal I/R injury. However, its role in renal I/R injury has not been fully elucidated. A mouse model of renal I/R injury was constructed by unilateral renal pedicle clamping and reperfusion. Mice undergoing I/R procedures exhibited renal function impairment and increased LRG protein expression compared with mice receiving sham operations. Tail vein injection with lentivirus carrying shLRG decreased renal I/R injury-induced increase in caspase-3 activity, IL-1β and IL-18 concentrations, and ROS production. Furthermore, shRNA-mediated LRG knockdown in HK-2 cells protected against H/R-induced cell damage. LRG could upregulate the expression of NADPH oxidase 4 (NOX4). We also determined the increased NOX4 expression in kidney tissues of renal I/R-operated mice and H/R-treated HK-2 cells. NOX4 overexpression reversed the inhibitory role of LRG knockdown in HK-2 cell damage caused by H/R. Collectively, our findings demonstrate that LRG knockdown decreases the NOX4 expression, thereby alleviating renal I/R injury by inhibiting cell apoptosis, inflammation, and oxidative stress.