Wang Jin-Hui, Mao Hai-Bo, Hu Jing-Bo, Cheng Shunhua, Su Hao
Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China.
Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
J Control Release. 2024 Dec;376:1100-1114. doi: 10.1016/j.jconrel.2024.10.063. Epub 2024 Nov 9.
Ischemia-reperfusion-induced acute kidney injury (IR-AKI) commonly occurs in situations such as hemorrhagic shock, kidney transplantation, and cardiovascular surgery. As one of the significant causes of AKI, IR-AKI is characterized by its high incidence and mortality rates. Currently, effective inflammation control is the key for the treatment of IR-AKI. In this study, we developed an ROS-responsive polymeric prodrugs (Zn-D/DTH) which could target the externalized PS of apoptotic cells, and then responsively released HDM (anti-inflammatory peptides) in the presence of intracellular ROS. Zn-D/DTH effectively ameliorated renal function and mitigated pathological alterations such as the loss of the brush border, tubular dilation, and accumulation of cellular debris within the tubular lumens. Furthermore, Zn-D/DTH greatly reduced the generation of pro-inflammatory factors like IL-6, COX-2, and iNOS in renal tissues, suggesting its protective role largely stems from suppression of the inflammatory response. Additional mechanism exploration revealed that Zn-D/DTH markedly decreased the expression levels of TLR4 and MyD88, as well as the phosphorylation of NF-κB in the damaged kidneys. This, in turn, reduced the number of apoptotic tubular cells and the activity of Caspase 9 and Caspase 3 caused by ischemia-reperfusion. Additionally, Zn-D/DTH treatment showed improvement in the long-term renal damage and fibrosis induced by ischemia-reperfusion. The experimental outcomes indicated that Zn-D/DTH attenuated renal ischemia-reperfusion injury and delayed the transition from acute kidney injury to chronic kidney disease by downregulating the TLR4/MyD88/NF-κB signaling pathway and reducing the expression of apoptotic caspases, thereby inhibiting inflammation and reducing cell apoptosis.
缺血再灌注诱导的急性肾损伤（IR-AKI）常见于出血性休克、肾移植和心血管手术等情况。作为急性肾损伤的重要原因之一，IR-AKI的特点是发病率和死亡率高。目前，有效控制炎症是治疗IR-AKI的关键。在本研究中，我们开发了一种ROS响应性聚合物前药（Zn-D/DTH），它可以靶向凋亡细胞外化的磷脂酰丝氨酸（PS），然后在细胞内ROS存在的情况下响应性释放HDM（抗炎肽）。Zn-D/DTH有效改善了肾功能，减轻了病理改变，如刷状缘丧失、肾小管扩张和肾小管腔内细胞碎片堆积。此外，Zn-D/DTH大大减少了肾组织中白细胞介素-6（IL-6）、环氧化酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）等促炎因子的产生，表明其保护作用主要源于对炎症反应的抑制。进一步的机制探索表明，Zn-D/DTH显著降低了受损肾脏中Toll样受体4（TLR4）和髓样分化因子88（MyD88）的表达水平，以及核因子κB（NF-κB）的磷酸化。这反过来又减少了缺血再灌注引起的凋亡肾小管细胞数量以及半胱天冬酶9（Caspase 9）和半胱天冬酶3（Caspase 3）的活性。此外，Zn-D/DTH治疗改善了缺血再灌注诱导的长期肾损伤和纤维化。实验结果表明，Zn-D/DTH通过下调TLR4/MyD88/NF-κB信号通路并降低凋亡半胱天冬酶的表达，从而抑制炎症和减少细胞凋亡，减轻了肾缺血再灌注损伤，并延缓了从急性肾损伤向慢性肾病的转变。
