From the Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China (C.L., D.Y., X.L., W.Y., G.L., X.C., Z.H.); and Department of Anesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China (H.L., M.G.I., Z.X.).
Anesthesiology. 2015 Jan;122(1):72-86. doi: 10.1097/ALN.0000000000000448.
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.
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).
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.
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.
肝移植后急性肾损伤（AKI）严重影响患者的生存，但其机制尚不清楚，也缺乏有效的治疗方法。作者推测，再灌注诱导的间隙连接蛋白 32（Cx32）间隙连接增强在介导肝移植后 AKI 中起关键作用，而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 Cx32 抑制剂 2-氨基乙氧基二苯硼酸盐或丙泊酚（50mg/kg）处理的情况下进行自体原位肝移植（AOLT）（每组 8 只）。此外，肾小管上皮（NRK-52E）细胞进行缺氧-复氧，通过三种不同的机制操纵 Cx32 的功能：细胞在不同密度下培养；用 Cx32 抑制剂或增强剂预处理；Cx32 基因敲低（n = 4 至 5）。
与假手术组相比，AOLT 导致肾 Cx32 蛋白表达和间隙连接明显增加，同时氧化应激增加，肾功能和组织损伤受损。同样，缺氧-复氧导致细胞损伤明显，表现为细胞生长减少和乳酸脱氢酶释放增加，Cx32 基因敲低可显著减轻，但 Cx32 增强可加剧。丙泊酚抑制 Cx32 功能并减轻肝移植后 AKI。在 NRK-52E 细胞中，丙泊酚减少了缺氧后活性氧的产生并减轻了细胞损伤，丙泊酚的细胞保护作用通过 Cx32 抑制得到加强，但通过 Cx32 增强而取消。
Cx32 在 AOLT 诱导的 AKI 中起关键作用，抑制 Cx32 功能可能是丙泊酚降低氧化应激并随后减轻肝移植后 AKI 的一个新的主要机制。
