Division of Nephrology, Sichuan Provincial People's Hospital& Sichuan Academy of Sciences, University of Electronic Science and Technology, China.
General Practice Center, Sichuan Academy of Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, 610072, China.
Int Immunopharmacol. 2024 May 30;133:112001. doi: 10.1016/j.intimp.2024.112001. Epub 2024 Apr 11.
Acute kidney injury (AKI) is a critical complication known for their extremely high mortality rate and lack of effective clinical therapy. Disorders in mitochondrial dynamics possess a pivotal role in the occurrence and progression of contrast-induced nephropathy (CIN) by activating NLRP3 inflammasome. The activation of dynamin-related protein-1 (Drp1) can trigger mitochondrial dynamic disorders by regulating excessive mitochondrial fission. However, the precise role of Drp1 during CIN has not been clarified. In vivo experiments revealed that inhibiting Drp1 through Mdivi-1 (one selective inhibitor of Drp1) can significantly decrease the expression of p-Drp1 (Ser616), mitochondrial p-Drp1 (Ser616), mitochondrial Bax, mitochondrial reactive oxygen species (mROS), NLRP3, caspase-1, ASC, TNF-α, IL-1β, interleukin (IL)-18, IL-6, creatinine (Cr), malondialdehyde (MDA), blood urea nitrogen (BUN), and KIM-1. Moreover, Mdivi-1 reduced kidney pathological injury and downregulated the interaction between NLRP3 and thioredoxin-interacting protein (TXNIP), which was accompanied by decreased interactions between TRX and TXNIP. This resulted in increasing superoxide dismutase (SOD) and CAT activity, TRX expression, up-regulating mitochondrial membrane potential, and augmenting ATP contents and p-Drp1 (Ser616) levels in the cytoplasm. However, it did not bring impact on the expression of p-Drp1 (Ser637) and TXNIP. Activating Drp-1though Acetaldehyde abrogated the effects of Mdivi-1. In addition, the results of in vitro studies employing siRNA-Drp1 and plasmid-Drp1 intervention in HK-2 cells treated with iohexol were consistent with the in vivo experiments. Our findings revealed inhibiting Drp1 phosphorylation at Ser616 could ameliorate iohexol -induced acute kidney injury though alleviating the activation of the TXNIP-NLRP3 inflammasome pathway.
急性肾损伤（AKI）是一种严重的并发症，其死亡率极高，且缺乏有效的临床治疗方法。线粒体动力学紊乱通过激活 NLRP3 炎性小体在对比剂诱导的肾病（CIN）的发生和进展中起着关键作用。动力相关蛋白 1（Drp1）的激活可以通过调节过度的线粒体裂变引发线粒体动力学紊乱。然而，Drp1 在 CIN 中的确切作用尚不清楚。体内实验表明，通过 Mdivi-1（Drp1 的一种选择性抑制剂）抑制 Drp1 可以显著降低 p-Drp1（Ser616）、线粒体 p-Drp1（Ser616）、线粒体 Bax、线粒体活性氧（mROS）、NLRP3、caspase-1、ASC、TNF-α、IL-1β、白细胞介素（IL）-18、IL-6、肌酐（Cr）、丙二醛（MDA）、血尿素氮（BUN）和 KIM-1 的表达。此外，Mdivi-1 减轻了肾脏病理损伤，并下调了 NLRP3 和硫氧还蛋白相互作用蛋白（TXNIP）之间的相互作用，同时降低了 TRX 和 TXNIP 之间的相互作用。这导致超氧化物歧化酶（SOD）和 CAT 活性增加，TRX 表达增加，线粒体膜电位增加，细胞质中 p-Drp1（Ser616）水平升高。然而，它对 p-Drp1（Ser637）和 TXNIP 的表达没有影响。用乙醛酸激活 Drp-1 会消除 Mdivi-1 的作用。此外，用 siRNA-Drp1 和质粒-Drp1 干预用碘海醇处理的 HK-2 细胞的体外研究结果与体内实验结果一致。我们的研究结果表明，抑制 Drp1 丝氨酸 616 的磷酸化可以通过减轻 TXNIP-NLRP3 炎性小体途径的激活来改善碘海醇诱导的急性肾损伤。
