Kuncewitch Michael, Yang Weng-Lang, Corbo Lana, Khader Adam, Nicastro Jeffrey, Coppa Gene F, Wang Ping
*Department of Surgery, Hofstra North Shore-LIJ School of Medicine; and †Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York.
Shock. 2015 Mar;43(3):268-75. doi: 10.1097/SHK.0000000000000293.
Renal ischemia-reperfusion (IR) injury (IRI) after shock states or transplantation causes tissue damage and delayed graft function, respectively. The Wnt/β-catenin signaling pathway plays a critical role in nephrogenesis. We therefore hypothesized that pharmacological activation of the Wnt/β-catenin signaling by the Wnt agonist, a synthetic pyrimidine, could protect kidneys from IRI. Adult male rats were subjected to bilateral clamping of the renal pedicles with microvascular clips for 60 min, followed by reperfusion. The Wnt agonist (5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) was administered intravenously 1 h before ischemia. Blood and renal tissues were collected 24 h after IR for evaluation. Renal IR caused a significant reduction of β-catenin and its downstream target gene cyclin D1 by 65% and 39%, respectively, compared with the sham, whereas the Wnt agonist restored them to sham levels. The number and intensity of cells staining with the proliferation marker Ki67 in ischematized kidneys were enhanced by the Wnt agonist. The integrity of the renal histological architecture in the Wnt agonist group was better preserved than the vehicle group. The Wnt agonist significantly lowered serum levels of creatinine, aspartate aminotransferase, and lactate dehydrogenase and inhibited the production of interleukin 6 and interleukin 1β and myeloperoxidase activities. Lastly, the Wnt agonist reduced inducible nitric oxide synthase, nitrotyrosine proteins, and 4-hydroxynonenal in the kidneys by 60%, 47%, and 21%, respectively, compared with the vehicle. These results indicate that the Wnt agonist improves renal regeneration and function while attenuating inflammation and oxidative stress in the kidneys after IR. Thus, pharmacologic stimulation of the Wnt/β-catenin signaling provides a beneficial effect on the prevention of renal IRI.
休克状态或移植后的肾缺血再灌注（IR）损伤（IRI）分别导致组织损伤和移植肾功能延迟。Wnt/β-连环蛋白信号通路在肾发生过程中起关键作用。因此，我们推测，由Wnt激动剂（一种合成嘧啶）对Wnt/β-连环蛋白信号进行药理学激活可保护肾脏免受IRI损伤。成年雄性大鼠用微血管夹双侧夹闭肾蒂60分钟，然后再灌注。在缺血前1小时静脉注射Wnt激动剂（5毫克/千克体重）或赋形剂（盐水中20%的二甲基亚砜）。IR后24小时收集血液和肾组织进行评估。与假手术组相比，肾IR使β-连环蛋白及其下游靶基因细胞周期蛋白D1分别显著降低65%和39%，而Wnt激动剂将它们恢复到假手术组水平。Wnt激动剂增强了缺血肾脏中用增殖标志物Ki67染色的细胞数量和强度。Wnt激动剂组肾组织学结构的完整性比赋形剂组保存得更好。Wnt激动剂显著降低血清肌酐、天冬氨酸转氨酶和乳酸脱氢酶水平，并抑制白细胞介素6和白细胞介素1β的产生以及髓过氧化物酶活性。最后，与赋形剂相比，Wnt激动剂使肾脏中的诱导型一氧化氮合酶、硝基酪氨酸蛋白和4-羟基壬烯醛分别减少60%、47%和21%。这些结果表明，Wnt激动剂可改善肾再生和功能，同时减轻IR后肾脏的炎症和氧化应激。因此，对Wnt/β-连环蛋白信号进行药理学刺激对预防肾IRI具有有益作用。
