Propofol Attenuated Acute Kidney Injury after Orthotopic Liver Transplantation via Inhibiting Gap Junction Composed of Connexin 32
Propofol Attenuated Acute Kidney Injury after Orthotopic Liver Transplantation via Inhibiting Gap Junction Composed of Connexin 32
复制标题
异丙酚通过抑制连接蛋白 32 组成的间隙连接减轻原位肝移植后的急性肾损伤。
DOI：
10.1097/aln.0000000000000448
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发表时间：
2015-01-01
期刊：
影响因子：
8.8
通讯作者：
Hei, Ziqing
中科院分区：
文献类型：
--
作者：
Luo, Chenfang;Yuan, Dongdong;Hei, Ziqing
背景资料：肝移植术后急性肾损伤（阿基）严重影响患者的生存，其机制尚不清楚，缺乏有效的治疗方法。作者推测，再灌注诱导的连接蛋白32（Cx 32）间隙连接增强在介导肝移植后阿基中起关键作用，并且已知抑制间隙连接的麻醉剂丙泊酚预处理/预处理可以提供有效的保护。雄性Sprague-Dawley大鼠在不存在或存在选择性Cx 32抑制剂治疗的情况下进行自体原位肝移植（AOLT），2-氨基乙氧基二苯基硼酸盐或丙泊酚（50 mg/kg）（每组n = 8）。另外，将肾小管上皮细胞（NRK-52 E）置于缺氧-复氧条件下，通过三种不同的机制来调控Cx 32的功能：不同密度的细胞培养; Cx 32抑制剂或增强剂预处理; Cx 32基因敲低（n = 4 ~ 5）。AOLT导致肾Cx 32蛋白表达和缝隙连接显著增加，与假手术组相比，这些变化与氧化应激增加、肾功能损害和组织损伤一致。同样，缺氧-复氧导致显著的细胞损伤，表现为细胞生长减少和乳酸脱氢酶释放增加，Cx 32基因敲低显著减弱，但Cx 32增强加重。丙泊酚抑制Cx 32功能并减轻AOLT后阿基。异丙酚可减少NRK-52 E细胞缺氧后活性氧的产生，减轻细胞损伤，抑制Cx 32可增强异丙酚的细胞保护作用，而增强Cx 32则可抵消异丙酚的细胞保护作用。Cx 32在AOLT诱导的阿基中起着关键作用，Cx 32功能的抑制可能代表了一种新的主要机制，即丙泊酚可降低氧化应激，随后减弱后ALT阿基。
Background: Postliver transplantation acute kidney injury (AKI) severely affects patient survival, whereas the mechanism is unclear and effective therapy is lacking. The authors postulated that reperfusion induced enhancement of connexin32 (Cx32) gap junction plays a critical role in mediating postliver transplantation AKI and that pretreatment/precondition with the anesthetic propofol, known to inhibit gap junction, can confer effective protection.Methods: Male Sprague-Dawley rats underwent autologous orthotopic liver transplantation (AOLT) in the absence or presence of treatments with the selective Cx32 inhibitor, 2-aminoethoxydiphenyl borate or propofol (50 mg/kg) (n = 8 per group). Also, kidney tubular epithelial (NRK-52E) cells were subjected to hypoxia-reoxygenation and the function of Cx32 was manipulated by three distinct mechanisms: cell culture in different density; pretreatment with Cx32 inhibitors or enhancer; Cx32 gene knock-down (n = 4 to 5).Results: AOLT resulted in significant increases of renal Cx32 protein expression and gap junction, which were coincident with increases in oxidative stress and impairment in renal function and tissue injury as compared to sham group. Similarly, hypoxia-reoxygenation resulted in significant cellular injury manifested as reduced cell growth and increased lactate dehydrogenase release, which was significantly attenuated by Cx32 gene knock-down but exacerbated by Cx32 enhancement. Propofol inhibited Cx32 function and attenuated post-AOLT AKI. In NRK-52E cells, propofol reduced posthypoxic reactive oxygen species production and attenuated cellular injury, and the cellular protective effects of propofol were reinforced by Cx32 inhibition but cancelled by Cx32 enhancement.Conclusion: Cx32 plays a critical role in AOLT-induced AKI and that inhibition of Cx32 function may represent a new and major mechanism whereby propofol reduces oxidative stress and subsequently attenuates post-AOLT AKI.