Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Int J Mol Sci. 2021 Feb 10;22(4):1764. doi: 10.3390/ijms22041764.
Endogenous factors involved in the progression of cisplatin nephropathy remain undetermined. Here, we demonstrate the toxico-pathological roles of indoxyl sulfate (IS), a sulfate-conjugated uremic toxin, and sulfotransferase 1A1 (SULT1A1), an enzyme involved in its synthesis, in cisplatin-induced acute kidney injury using -deficient ( KO) mice. With cisplatin administration, severe kidney dysfunction, tissue damage, and apoptosis were attenuated in (KO) mice. Aryl hydrocarbon receptor (AhR) expression was increased by treatment with cisplatin in mouse kidney tissue. Moreover, the downregulation of antioxidant stress enzymes in wild-type (WT) mice was not observed in (KO) mice. To investigate the effect of IS on the reactive oxygen species (ROS) levels, HK-2 cells were treated with cisplatin and IS. The ROS levels were significantly increased compared to cisplatin or IS treatment alone. IS-induced increases in ROS were reversed by downregulation of AhR, xanthine oxidase (XO), and NADPH oxidase 4 (NOX4). These findings suggest that SULT1A1 plays toxico-pathological roles in the progression of cisplatin-induced acute kidney injury, while the IS/AhR/ROS axis brings about oxidative stress.
内源性因素在顺铂肾毒性进展中的作用仍不确定。在这里，我们使用 SULT1A1 缺乏（KO）小鼠来证明硫酸吲哚酚（IS）——一种硫酸盐结合的尿毒症毒素，以及参与其合成的酶磺基转移酶 1A1（SULT1A1）在顺铂诱导的急性肾损伤中的毒理作用。在给予顺铂后，KO 小鼠的严重肾功能障碍、组织损伤和细胞凋亡减轻。顺铂处理增加了小鼠肾组织中的芳烃受体（AhR）表达。此外，在 WT 小鼠中未观察到抗氧化应激酶的下调，而在 KO 小鼠中则没有。为了研究 IS 对活性氧（ROS）水平的影响，用顺铂和 IS 处理 HK-2 细胞。与单独用顺铂或 IS 处理相比，ROS 水平显著增加。下调 AhR、黄嘌呤氧化酶（XO）和 NADPH 氧化酶 4（NOX4）可逆转 IS 诱导的 ROS 增加。这些发现表明，SULT1A1 在顺铂诱导的急性肾损伤进展中发挥毒理作用，而 IS/AhR/ROS 轴则导致氧化应激。
