Zhou Li-Bin, Peng Xuan-Ze, Long Hui-Min, Hu Jing-Bo, Xu Jian-Ting
Department of Urology, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, 315040, China.
Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China.
Mater Today Bio. 2025 Aug 19;34:102207. doi: 10.1016/j.mtbio.2025.102207. eCollection 2025 Oct.
Acute kidney injury (AKI) is characterized by a sudden decline in kidney function, often due to ischemia-reperfusion or nephrotoxic drugs. A key factor in AKI development is mitochondrial dysfunction, which disrupts energy and oxygen supply, increases ROS generation, and triggers inflammation. Addressing AKI through mitochondrial targeting remains challenging. Melatonin (MLT), a hormone secreted by the pineal gland, shows promise in AKI treatment. To enhance site-specific antioxidative efficacy, triphenylphosphonium-hyaluronic acid (TPP-HA), targeting CD44 receptors and mitochondria, was synthesized and linked to MLT via a cleavable linker, creating TPP-HA-TK-MLT (THTM). THTM improved MLT targeting in renal tubular epithelial cells through CD44 receptors and enhanced mitochondrial distribution via TPP. This effectively suppressed mitochondrial ROS under pathological conditions, ameliorated mitochondrial permeability and swelling, and increased resistance to stimuli such as ischemia-reperfusion injury or nephrotoxic drugs, reducing cell apoptosis. Moreover, THTM significantly reduced the progression of folic acid-induced kidney injury to chronic kidney disease, demonstrating its potential to lower the risk of chronic kidney disease.
急性肾损伤（AKI）的特征是肾功能突然下降，通常是由于缺血再灌注或肾毒性药物所致。AKI发生发展的一个关键因素是线粒体功能障碍，它会破坏能量和氧气供应，增加活性氧（ROS）的生成，并引发炎症。通过靶向线粒体来治疗AKI仍然具有挑战性。褪黑素（MLT）是一种由松果体分泌的激素，在AKI治疗中显示出前景。为了增强位点特异性抗氧化功效，合成了靶向CD44受体和线粒体的三苯基膦-透明质酸（TPP-HA），并通过可裂解连接子将其与MLT相连，从而产生了TPP-HA-TK-MLT（THTM）。THTM通过CD44受体改善了肾小管上皮细胞中MLT的靶向性，并通过TPP增强了线粒体分布。这在病理条件下有效抑制了线粒体ROS，改善了线粒体通透性和肿胀，并增加了对缺血再灌注损伤或肾毒性药物等刺激的抗性，减少了细胞凋亡。此外，THTM显著降低了叶酸诱导的肾损伤向慢性肾病的进展，证明了其降低慢性肾病风险的潜力。
