背景:急性肾损伤(AKI)导致远处肝损伤,到目前为止,这导致AKI患者的不良预后。已经进行了许多研究来克服AKI相关的肝损伤。然而,这些研究主要集中在肝细胞上,AKI引起的肝损伤仍然是一个临床问题。这里,我们研究了胆管细胞及其初级纤毛的含义,这对最终胆汁分泌至关重要。胆管细胞,胆管的衬里细胞,是唯一含有原代纤毛(基于微管的细胞表面信号感应细胞器)的肝上皮细胞。
方法:谷胱甘肽γ-裂解酶(CSE,对转硫酶)缺陷和野生型小鼠进行肾缺血,然后再灌注(KIR)。向一些小鼠施用N-乙酰半胱氨酸(NAC)。
结果:KIR损伤肝细胞和胆管癌,破裂的胆管细胞初级纤毛,将破碎的纤毛碎片释放到胆汁中,并导致胆汁分泌异常。谷胱甘肽(GSH)和H2S水平在肝脏中显著降低,导致氧化GSH与总GSH的比率增加,以及组织和胆汁的氧化。KIR后,肝脏中CSE和谷胱甘肽β-合酶(CBS)的表达降低。NAC给药增加了肝脏中的总GSH和H2S水平,并减轻了KIR引起的肝损伤。相比之下,Cse缺失导致总GSH水平降低,并恶化KIR诱导的肝损伤,包括原发性纤毛损害和胆汁分泌异常。
结论:这些结果表明KIR引起胆管细胞损伤,胆管细胞初级纤毛破坏,和胆汁分泌异常通过降低肝脏的抗氧化能力。
Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle).
Cystathione γ-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC).
KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione β-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion.
These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.