Date Published: August 16, 2018
Publisher: Public Library of Science
Author(s): Seung Hyun Kim, Ji Hae Jun, Ju Eun Oh, Eun-Jung Shin, Young Jun Oh, Yong Seon Choi, Ferenc Gallyas.
Diabetic patients are susceptible to renal ischemia-reperfusion injury, which leads to perioperative complications. Activation of NOD-like receptor protein 3 (NLRP3) inflammasome participates in the development of diabetes, and contributes to renal ischemia-reperfusion injury. Dexmedetomidine (DEX), a highly selective α2-adrenoreceptor agonist, shows renoprotective effects against ischemia-reperfusion injury. We aimed to elucidate the effects, underlying mechanisms, and optimal timing of DEX treatment in diabetic rats.
Male Sprague-Dawley rats (n = 12 per group) were randomly divided into normal-sham, diabetes-sham, diabetes-ischemia-reperfusion-control, diabetes-ischemia-reperfusion-DEX-pre-treatment, and diabetes-ischemia-reperfusion-DEX-post-treatment groups. Renal ischemia-reperfusion injury was induced in diabetic rats by occlusion of both renal arteries for 45 min, followed by reperfusion for 24 h. DEX (10 μg/kg) was administered intraperitoneally 1 h before ischemia (pre-treatment) or upon reperfusion (post-treatment). After reperfusion, renal tissue was biochemically and histopathologically evaluated.
DEX treatment attenuated ischemia reperfusion-induced increase in NLRP3, caspase-1, IL-1β, phospho-AKT, and phospho-ERK signaling. Moreover, oxidative stress injury, inflammatory reactions, apoptosis, and renal tubular damage were favorably modulated by DEX treatment. Furthermore, post-reperfusion treatment with DEX was significantly more effective than pre-treatment in modulating NLRP3 inflammasome, AKT and ERK signaling, and oxidative stress.
This study shows that the protective effects of DEX in renal ischemia-reperfusion injury are preserved in diabetic conditions and may potentially provide a basis for the use of DEX in clinical treatment of renal ischemia-reperfusion injury.
Acute kidney injury (AKI) is a common complication during major surgeries and is associated with increased risk of chronic kidney disease and mortality . Diabetes mellitus is a metabolic disorder with major complications, including microvascular and macrovascular diseases, and an important risk factor for AKI resulting in renal damage and dysfunction, as it increases susceptibility to ischemia-reperfusion (IR) injury .
This is the first study to demonstrate that the renoprotective effects of DEX in renal IR injury are associated with inflammasomes in a diabetic rat model. Renal IR injury increased the levels of inflammasome components NLRP3 and caspase-1, an effect reversible by DEX. DEX also reduced increased IL-1βlevels, activated by NLRP3 inflammasome. NLRP3 inflammasome-associated protective effect of DEX was greater in the post-reperfusion treatment group than in the pre-treatment group. Post-reperfusion DEX treatment was also more effective than pre-treatment in terms of AKT and ERK signaling, oxidative stress, and renal dysfunction.
This study showed that the protective effects of DEX in renal IR injury are preserved under diabetic conditions and are related to inflammasomes. Furthermore, post-reperfusion DEX treatment was more effective than pre-ischemia treatment. These findings potentially provide a basis for using DEX in treating renal IR injury.