Figure 8
From: Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice
Putative mechanism of dexmedetomidine (Dex) renoprotection. Dexmedetomidine stimulates the α2 adrenoceptor (α2) to induce phosphoinositol-3-kinase (PI3K) phosphorylation of Akt (pAKT) and activation of the downstream cell survival signaling to block ischemia induced injury. Ischemia is denoted by the "flash" symbol. Improved cellular survival leads to reduced release of the damage-associated molecular pattern High-mobility group protein B1 (HMGB1). Reduced HMGB1 decreases the inflammatory drive that both increases Toll-like receptor 4 (TLR4) expression and activates the detrimental effect of TLR4 signaling in renal ischemia. Co-receptors for HMGB1 include TLRs and Interleukin-1 (IL-1) receptor; when HMGB1 binds to the ligand (for example, lipopolysaccharide or IL-1) this augments subsequent proinflammatory signaling. Therefore, dexmedetomidine acts proximally in the pathway (at the cytoprotective level) to prevent the elaboration of renal ischemic injury. 'Lightening bolt' denotes ischemia. 'Square' denotes HMGB1 co-receptor.