15-Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast-induced acute kidney injury.
15-Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast-induced acute kidney injury.
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DOI：
10.1080/0886022x.2020.1870139
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发表时间：
2021-12
期刊：
影响因子：
3
通讯作者：
Bae KB
中科院分区：
文献类型：
--
作者：
Kim BW;Kim HJ;Kim SH;Baik HJ;Kang MS;Kim DH;Markowitz SD;Kang SW;Bae KB
碘造影剂（CM）引起造影剂急性肾损伤（CIAKI）的两个主要机制是引起肾内血管收缩的血流动力学效应和引起急性肾小管坏死的肾小管毒性作用。抑制 15-羟基前列腺素脱氢酶 (15-PGDH) 可降解前列腺素 E2 (PGE2)，促进许多器官的组织修复和再生。 PGE2 引起肾内动脉血管舒张。在本研究中，我们研究了 15-PGDH 抑制剂是否可以作为阻断 CIAKI 这两个主要机制的候选药物。我们通过向每只小鼠尾静脉注射每体重 10 克碘 (gI/kg) 剂量的碘克沙醇来建立 CIAKI 小鼠模型。给予 15-PGDH 抑制剂 (SW033291)、PGE1 或 PGE2 来比较肾功能参数、组织学损伤、血管收缩和肾血流变化。此外，人肾近端肾小管上皮细胞在CM处理的培养基中培养。添加 SW033291、PGE1 或 PGE2 以比较细胞活力和凋亡率的任何变化。接受 SW033291 治疗的 CIAKI 小鼠血清肌酐、中性粒细胞明胶酶相关脂质运载蛋白和肾损伤分子 1 水平较低（p<<0.001）；较低的组织学损伤评分和 TUNEL 阳性率 (p < 0.001)；与 CM + 载体组相比，髓小动脉面积 (p < 0.05) 和肾血流量 (p < 0.001) 更高。在细胞培养实验中，添加SW033291增加了肾小管上皮细胞的存活率（p< 0.05）并降低了肾小管上皮细胞的凋亡率（p< 0.001）。这种 15-PGDH 抑制剂可阻断 CIAKI 的两种主要机制，即肾内血管收缩和肾小管细胞毒性，因此有可能成为 CIAKI 的新型预防药物。缩写：15-PGDH：15-羟基前列腺素脱氢酶； AMP：单磷酸腺苷； CIAKI：对比剂诱发的急性肾损伤； CM：造影剂； EP：前列腺素E2受体； hRPTECs：人源肾近曲小管上皮细胞； KIM-1：肾损伤分子-1； MTT：3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑； NGAL：中性粒细胞明胶酶相关脂质运载蛋白； PBS：磷酸盐缓冲盐水； PGE1：前列腺素E1； PGE2：前列腺素E2； RBF：肾血流量； TUNEL：末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记； α-SMA：α-平滑肌肌动蛋白
The two primary mechanisms by which iodinated contrast media (CM) causes contrast-induced acute kidney injury (CIAKI) are the hemodynamic effect causing intrarenal vasoconstriction and the tubular toxic effect causing acute tubular necrosis. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades prostaglandin E2 (PGE2), promotes tissue repair and regeneration in many organs. PGE2 causes intrarenal arterial vasodilation. In this study, we investigated whether a 15-PGDH inhibitor can act as a candidate for blocking these two major mechanisms of CIAKI. We established a CIAKI mouse model by injecting a 10 gram of iodine per body weight (gI/kg) dose of iodixanol into each mouse tail vein. A 15-PGDH inhibitor (SW033291), PGE1, or PGE2 were administered to compare the renal functional parameters, histologic injury, vasoconstriction, and renal blood flow changes. In addition, human renal proximal tubular epithelial cells were cultured in a CM-treated medium. SW033291, PGE1, or PGE2 were added to compare any changes in cell viability and apoptosis rate. CIAKI mice that received SW033291 had lower serum levels of creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1 (p < 0.001); lower histologic injury score and TUNEL positive rates (p < 0.001); and higher medullary arteriolar area (p < 0.05) and renal blood flow (p < 0.001) than CM + vehicle group. In cell culture experiments, Adding SW033291 increased the viability rate (p < 0.05) and decreased the apoptosis rate of the tubular epithelial cells (p < 0.001). This 15-PGDH inhibitor blocks the two primary mechanisms of CIAKI, intrarenal vasoconstriction and tubular cell toxicity, and thus has the potential to be a novel prophylaxis for CIAKI. Abbreviations: 15-PGDH: 15-hydroxyprostaglandin dehydrogenase; AMP: adenosine monophosphate; CIAKI: contrast-induced acute kidney injury; CM: contrast media; EP: prostaglandin E2 receptor; hRPTECs: human-derived renal proximal tubule epithelial cells; KIM-1: kidney injury molecule-1; MTT: 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NGAL: neutrophil gelatinase-associated lipocalin; PBS: phosphate-buffered saline; PGE1: prostaglandin E1; PGE2: prostaglandin E2; RBF: renal blood flow; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; α-SMA: α-Smooth muscle actin