Department of Urology/Medical Research and Education, Taipei Veterans General Hospital, Yuan-Shan Branch, Yilan, Taiwan; Department of Urology, National Taiwan University Hospital, Taipei, Taiwan; Department of Nursing, Cardinal Tien Junior College of Healthcare and Management, New Taipei, Taiwan.
Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Life Sci. 2023 Aug 15;327:121863. doi: 10.1016/j.lfs.2023.121863. Epub 2023 Jun 16.
The enhancement of inflammation and reactive oxygen species leads to the damage of renal tubular cells in acute kidney injury (AKI), and the upregulation of inflammation increases the risk of AKI being converted into chronic kidney disease (CKD). Hydralazine has shown renoprotective effects in multiple kidney diseases and was shown to be a potent xanthine oxidase (XO) inhibitor. This study aimed to investigate the mechanisms of hydralazine in ischemia-reperfusion (I/R)-stimulated renal proximal tubular epithelial cells in vitro and in AKI animals in vivo.
The effects of hydralazine in AKI-to-CKD transition were also evaluated. Human renal proximal tubular epithelial cells were stimulated by I/R conditions in vitro. To generate a mouse model of AKI, a right nephrectomy was performed, followed by left renal pedicle I/R using a small atraumatic clamp.
In the in vitro part, hydralazine could protect renal proximal tubular epithelial cells against insults from the I/R injury through XO/NADPH oxidase inhibition. In the in vivo part, hydralazine preserved renal function in AKI mice and improved the AKI-to-CKD transition by decreasing renal glomerulosclerosis and fibrosis independently of blood pressure lowering. Furthermore, hydralazine exerted antioxidant, anti-inflammatory, and anti-fibrotic effects both in vitro and in vivo.
Hydralazine, as a XO/NADPH oxidase inhibitor, could protect renal proximal tubular epithelial cells from the insults of I/R and prevent kidney damage in AKI and AKI-to-CKD. The above experimental studies strengthen the possibility of repurposing hydralazine as a potential renoprotective agent through its antioxidative mechanisms.
炎症和活性氧的增强导致急性肾损伤（AKI）中的肾小管细胞损伤，炎症的上调增加了 AKI 转化为慢性肾脏病（CKD）的风险。肼屈嗪在多种肾脏疾病中显示出肾保护作用，并且被证明是一种有效的黄嘌呤氧化酶（XO）抑制剂。本研究旨在探讨肼屈嗪在体外缺血再灌注（I/R）刺激的肾近端管状上皮细胞和体内 AKI 动物中的作用机制。
还评估了肼屈嗪在 AKI 向 CKD 转化中的作用。人肾近端管状上皮细胞在体外通过 I/R 条件刺激。为了生成 AKI 小鼠模型，进行右肾切除术，然后使用小无创伤夹对左肾蒂进行 I/R。
在体外部分，肼屈嗪通过抑制 XO/NADPH 氧化酶来保护肾近端管状上皮细胞免受 I/R 损伤的侵害。在体内部分，肼屈嗪通过降低肾小球硬化和纤维化，独立于降压作用，在 AKI 小鼠中保护肾功能并改善 AKI 向 CKD 的转化。此外，肼屈嗪在体外和体内均发挥抗氧化、抗炎和抗纤维化作用。
作为 XO/NADPH 氧化酶抑制剂，肼屈嗪可保护肾近端管状上皮细胞免受 I/R 的侵害，并预防 AKI 和 AKI 向 CKD 的肾脏损伤。上述实验研究通过其抗氧化机制，增强了将肼屈嗪重新用作潜在肾保护剂的可能性。
