General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria.
Faculty of Medicine, Vilnius University, 01513 Vilnius, Lithuania.
Int J Mol Sci. 2021 Oct 22;22(21):11417. doi: 10.3390/ijms222111417.
Ischemia-reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing outcomes. Relaxin-2 (RLX) is a promising insulin-related peptide hormone that protects against renal IRI in rodents, although large animal models are needed before RLX can be tested in a human setting. In this blinded, randomized, and placebo-controlled experimental study kidneys from 19 donor pigs were retrieved after perfusion with Custodiol ± RLX (5 or 20 nmol/L) and underwent static cold storage (SCS) for 24 and 48 h, respectively. Subsequently, KT was performed after unilateral right nephrectomy. Study outcomes included markers for kidney function, oxidative stress, lipid peroxidation, and endothelial cell damage. PCR analysis for oxidative stress and apoptosis-related gene panels as well as immunohistochemistry were performed. RLX upregulated SOD2 and NFKB expression to 135% ( = 0.042) and 125% ( = 0.019), respectively, while RIPK1 expression was downregulated to 82% ( = 0.016) of corresponding controls. Further RLX significantly downregulated RIPK1 and MLKL expression and decreased the number of Caspase 3- and MPO-positive cells in grafts after SCS. RLX supplemented Custodiol significantly decreased IRI via both antioxidant and anti-apoptotic mechanisms. Clinical trials are warranted to implement synthetic human RLX as a novel additive to preservation solutions against IRI.
缺血再灌注损伤（IRI）是肾移植（KT）后不可避免的，会损害预后。松弛素-2（RLX）是一种有前途的与胰岛素相关的肽类激素，可在啮齿动物中保护肾脏免受 IRI 的影响，但在 RLX 可以在人类环境中进行测试之前，需要大型动物模型。在这项盲法、随机和安慰剂对照的实验研究中，19 头供体猪的肾脏在接受 Custodiol ± RLX（5 或 20 nmol/L）灌注后被取出，并分别进行 24 和 48 小时的静态冷保存（SCS）。随后，在单侧右肾切除术后进行 KT。研究结果包括肾功能、氧化应激、脂质过氧化和内皮细胞损伤的标志物。进行了 PCR 分析以检测氧化应激和凋亡相关基因谱，并进行了免疫组织化学染色。RLX 将 SOD2 和 NFKB 的表达上调至 135%（=0.042）和 125%（=0.019），而 RIPK1 的表达下调至 82%（=0.016），与相应的对照相比。进一步的 RLX 显著下调了 RIPK1 和 MLKL 的表达，并减少了 SCS 后移植物中 Caspase 3-和 MPO 阳性细胞的数量。Custodiol 中添加 RLX 通过抗氧化和抗凋亡机制显著减轻了 IRI。需要进行临床试验，以将合成的人类 RLX 作为一种新型添加剂纳入保存液，以对抗 IRI。
