Department of Pathological and Molecular Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Division of Pharmacology, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
Oxid Med Cell Longev. 2022 Feb 25;2022:7547269. doi: 10.1155/2022/7547269. eCollection 2022.
Chronic kidney disease (CKD) and cardiovascular disease are known to be linked, and the involvement of indoxyl sulfate (IS), a type of uremic toxin, has been suggested as one of the causes. It is known that IS induces vascular dysfunction through overproduction of reactive oxygen species (ROS). On the other hand, the involvement of IS in the vascular dysfunction associated with acute kidney injury (AKI) is not fully understood. Therefore, we investigated this issue using the thoracic aorta of rats with ischemic AKI. Ischemic AKI was induced by occlusion of the left renal artery and vein for 45 min, followed by reperfusion 2 weeks after contralateral nephrectomy. One day after reperfusion, there was marked deterioration in renal function evidenced by an increase in plasma creatinine. Furthermore, blood IS levels increased markedly due to worsening renal function. Seven days and 28 days after reperfusion, blood IS levels decreased with the improvement in renal function. Of note, acetylcholine-induced vasorelaxation deteriorated over time after reperfusion, contradicting the recovery of renal function. In addition, 28 days after reperfusion, we observed a significant increase in ROS production in the vascular tissue. Next, we administered AST-120, a spherical adsorbent charcoal, after reperfusion to assess whether the vascular endothelial dysfunction associated with the ischemic AKI was due to a temporary increase in blood IS levels. AST-120 reduced the temporary increase in blood IS levels after reperfusion without influencing renal function, but did not restore the impaired vascular reactivity. Thus, in ischemic AKI, we confirmed that the vascular endothelial function of the thoracic aorta is impaired even after the recovery of kidney injury, probably with excessive ROS production. IS, which increases from ischemia to early after reperfusion, may not be a major contributor to the vascular dysfunction associated with ischemic AKI.
慢性肾脏病（CKD）和心血管疾病是已知的相关联的，而一种尿毒症毒素——硫酸吲哚酚（IS）的参与被认为是其中的一个原因。已知 IS 通过产生过多的活性氧物种（ROS）诱导血管功能障碍。另一方面，IS 与急性肾损伤（AKI）相关的血管功能障碍的参与尚不完全清楚。因此，我们使用缺血性 AKI 大鼠的胸主动脉研究了这个问题。缺血性 AKI 通过左肾动静脉闭塞 45 分钟诱导，然后在对侧肾切除 2 周后再灌注。再灌注后 1 天，肾功能明显恶化，表现为血浆肌酐升高。此外，由于肾功能恶化，血液 IS 水平显著增加。再灌注后 7 天和 28 天，随着肾功能的改善，血液 IS 水平下降。值得注意的是，再灌注后乙酰胆碱诱导的血管舒张随时间恶化，与肾功能的恢复相矛盾。此外，再灌注 28 天后，我们观察到血管组织中 ROS 产生显著增加。接下来，我们在再灌注后给予 AST-120（一种球形吸附炭），以评估与缺血性 AKI 相关的血管内皮功能障碍是否是由于血液 IS 水平的暂时升高引起的。AST-120 降低了再灌注后血液 IS 水平的暂时性升高，而不影响肾功能，但没有恢复受损的血管反应性。因此，在缺血性 AKI 中，我们证实即使在肾损伤恢复后，胸主动脉的血管内皮功能也会受损，可能是由于 ROS 产生过多。从缺血到再灌注早期增加的 IS 可能不是与缺血性 AKI 相关的血管功能障碍的主要原因。
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