Dexmedetomidine preconditioning ameliorates kidney ischemia‐reperfusion injury

Abstract

Kidney ischemia-reperfusion (I/R) injury is a common cause of acute kidney injury. We tested whether dexmedetomidine (Dex), an alpha2 adrenoceptor (α2-AR) agonist, protects against kidney I/R injury. Sprague–Dawley rats were divided into four groups: (1) Sham-operated group; (2) I/R group (40 min ischemia followed by 24 h reperfusion); (3) I/R group + Dex (1 μg/kg i.v. 60 min before the surgery), (4) I/R group + Dex (10 μg/kg). The effects of Dex postconditiong (Dex 1 or 10 μg/kg i.v. after reperfusion) as well as the effects of peripheral α2-AR agonism with fadolmidine were also examined. Hemodynamic effects were monitored, renal function measured, and acute tubular damage along with monocyte/macrophage infiltration scored. Kidney protein kinase B, toll like receptor 4, light chain 3B, p38 mitogen-activated protein kinase (p38 MAPK), sirtuin 1, adenosine monophosphate kinase (AMPK), and endothelial nitric oxide synthase (eNOS) expressions were measured, and kidney transciptome profiles analyzed. Dex preconditioning, but not postconditioning, attenuated I/R injury-induced renal dysfunction, acute tubular necrosis and inflammatory response. Neither pre- nor postconditioning with fadolmidine protected kidneys. Dex decreased blood pressure more than fadolmidine, ameliorated I/R-induced impairment of autophagy and increased renal p38 and eNOS expressions. Dex downregulated 245 and upregulated 61 genes representing 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in particular, integrin pathway and CD44. Ingenuity analysis revealed inhibition of Rac and nuclear factor (erythroid-derived 2)-like 2 pathways, whereas aryl hydrocarbon receptor (AHR) pathway was activated. Dex preconditioning ameliorates kidney I/R injury and inflammatory response, at least in part, through p38-CD44-pathway and possibly also through ischemic preconditioning.

Tanshinone IIA pretreatment attenuates ischemia/reperfusion-induced renal injury

“…Furthermore, it can activate MAPK activator protein kinase 2 and 3, and caspase family members (37). The combination of activated transcription factor and cis-regulatory elements may result in substantial genetic expression associated with apoptosis and is closely related to delayed neuronal death (36). The present results showed tanshinone IIA significantly reduced the elevation of p-p38 MAPK protein expression in I/RIRI rats.…”

“…MAPK family is a signal conditioning enzyme connecting AFP receptor and dominant gene expression (36). It may be activated in cases of external stimulation, such as hypoxic-ischemic, inflammation, low oxygen and aglycemia.…”

“…P38 MAPK is present within the cytoplasm, and when activated it is rapidly transferred into the nucleus and takes action on corresponding targets within cells (37). It can activate inferior kinase or a variety of transcriptional regulatory factors, such as ATF-2, Elk-1, CHOP10 and MEF-2C (36,37). Furthermore, it can activate MAPK activator protein kinase 2 and 3, and caspase family members (37).…”

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

“…Dex is known to be protective against IR in various organs including the kidneys, lung, brain and liver [14,[40][41][42]. The cardiac preconditioning effect of…”

Role of Intravenous Dexmedetomidine in Prolonging Postoperative Analgesia and Quality of Block Following Spinal Anaesthesia. A Systemic Review and Update

“…Dexmedetomidine has been shown to have organ protective effects in animal models particularly in modulation of cytokine and inflammatory mediators in variety of ischaemia and ischemic-reperfusion injury in animal [78][79][80][81][82][83]. However, such protective effects are not evident in human studies.…”