Soluble receptor for advanced glycation end products attenuates sepsis-associated acute kidney injury.

Receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous inflammatory conditions including sepsis. We investigated the possible therapeutic role of soluble RAGE (sRAGE) in septic acute kidney injury (AKI) models. sRAGE level was measured in healthy controls and patients with septic AKI. C57/BL6 mice with cecal ligation and puncture (CLP) were injected with sRAGE (CLP + sRAGE) 1 hour before the operation. NRK-52E cells were treated with lipopolysaccharide (LPS, 1 μg/mL) and sRAGE (1 μg/mL) or RAGE small interfering RNA. RAGE-associated signaling molecule and apoptosis-related protein (ARP) expression levels were analyzed. Serum sRAGE level was significantly higher in septic AKI patients than in healthy controls, and higher sRAGE level was associated with better survival rates. Blood urea nitrogen and creatinine levels were significantly higher in CLP mice than controls, and these increases were significantly abrogated in CLP + sRAGE mice. Renal MyD88 and phospho-ERK, -p38, and -JNK proteins and ARP expression levels in the CLP group were also significantly increased compared to controls, and these changes were significantly ameliorated by sRAGE treatment in CLP mice. In vitro, RAGE-associated activation of mitogen-activated protein kinase and ARP expression in LPS-stimulated cells were significantly ameliorated by sRAGE. Furthermore, the increases in nuclear factor kappa B nuclear translocation and intercellular adhesion molecule 1 protein expression by LPS were significantly attenuated by sRAGE in these cells. These findings suggest that RAGE plays an important role in septic AKI, and its inhibition by sRAGE may be a potential therapeutic target for AKI in severe sepsis.