Department of Intensive Care Unit, The First Affiliated Hospital of Huzhou Normal College, Huzhou, 313000, Zhejiang, PR China.
Department of Intensive Care Unit, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China.
Biochem Biophys Res Commun. 2021 May 21;554:158-165. doi: 10.1016/j.bbrc.2021.03.103. Epub 2021 Mar 31.
Ascorbate (Vitamin C) has been proposed as a promising therapeutic agent against sepsis in clinical trials, but there is little experimental evidence on its anti-septic efficacy. We report that Toll-like receptor 4 (TLR4) activation by LPS stimuli augments ascorbate uptake in murine and human tubular cells through upregulation of two ascorbate transporters SVCT-1 and -2 mediated by Fn14/SCF cascade. Ascorbate restriction, or knockout of SVCT-1 and -2, the circumstance reminiscent to blockade of ascorbate uptake, endows tubular cells more vulnerable to the LPS-inducible apoptosis, whereas exogenous administration of ascorbate overrides the ruin execution, for which the PINK1-PARK2, rather than BNIP3-NIX axis is required. Ascorbate increases, while SVCT-1 and -2 knockout or ascorbate restriction dampens tubular mitophagy upon LPS stimuli. Treatment of endotoxemic mice with high-dose ascorbate confers mitophagy and substantial protection against mortality and septic acute kidney injury (AKI). Our work provides a rationale for clinical management of septic AKI with high doses of ascorbate.
抗坏血酸（维生素 C）在临床试验中被提议作为一种有前途的治疗败血症的药物，但几乎没有关于其抗败血症疗效的实验证据。我们报告，LPS 刺激物通过 Toll 样受体 4（TLR4）激活，通过 Fn14/SCF 级联上调两种抗坏血酸转运蛋白 SVCT-1 和 -2，增加鼠和人肾小管细胞中的抗坏血酸摄取。抗坏血酸限制或 SVCT-1 和 -2 的敲除，这种情况类似于抗坏血酸摄取的阻断，使肾小管细胞更容易受到 LPS 诱导的凋亡，而外源性给予抗坏血酸则可以克服这种破坏作用，其中需要 PINK1-PARK2 而不是 BNIP3-NIX 轴。在 LPS 刺激下，抗坏血酸增加，而 SVCT-1 和 -2 敲除或抗坏血酸限制则抑制肾小管自噬。用大剂量抗坏血酸治疗内毒素血症小鼠可诱导自噬，并对死亡率和败血症急性肾损伤（AKI）有显著保护作用。我们的工作为临床管理败血症 AKI 提供了使用大剂量抗坏血酸的依据。
