Xie Lulu, Zhang Kaiyue, Pan Kai, Su Xiaomin, Zhao Xiaotong, Li Rui, Wang Yixin, Pang Haotian, Fu Enze, Li Zongjin
School of Medicine, Nankai University, Tianjin, 300071, China.
Columbia University, New York, 10027-6902, US.
J Transl Med. 2025 Mar 10;23(1):304. doi: 10.1186/s12967-025-06268-x.
Acute kidney injury (AKI) is a common and severe clinical condition. However, the underlying mechanisms of AKI have not been fully elucidated, and effective treatment options remain limited. Studies have shown that immune cells play a critical role in AKI, with regulatory T cells (Tregs) being one of the most important immunosuppressive lymphocytes. Tregs proliferation can attenuate AKI, whereas depletion exacerbates kidney injury. Given that endothelial cells (ECs) are the initial cells that interact with immune cells when they invade the tissue parenchyma, ECs are closely associated with immune reactions.
In this study, P-selectin binding peptide-extracellular vesicles (PBP-EVs) that target and repair ECs are engineered. Transcriptome sequencing reveals that PBP-EVs reduce the expression of inflammatory genes in AKI mice. Using high-resolution intravital two-photon microscopy (TPM), an increased recruitment of Tregs in the kidneys of AKI Foxp3-EGFP transgenic mice following PBP-EVs treatment is observed, as well as significant Lgr5 renal stem cell proliferation in AKI Lgr5-Cre; R26 mice. Additionally, PBP-EVs treatment result in reduced infiltration of inflammatory cells, pathological damage and fibrosis of AKI mice. Upon depletion of Tregs in Foxp3-DTR transgenic mice, we observe diminished therapeutic effect of PBP-EVs on AKI.
The experimental results indicate that PBP-EVs can promote the repair and regeneration of AKI by mitigating endothelial cell damage and subsequently modulating Tregs and the immune microenvironment. These findings provide novel insights and strategies for the treatment of AKI.
急性肾损伤（AKI）是一种常见且严重的临床病症。然而，AKI的潜在机制尚未完全阐明，有效的治疗选择仍然有限。研究表明，免疫细胞在AKI中起关键作用，调节性T细胞（Tregs）是最重要的免疫抑制淋巴细胞之一。Tregs增殖可减轻AKI，而耗竭则会加重肾损伤。鉴于内皮细胞（ECs）是免疫细胞侵入组织实质时与之相互作用的初始细胞，ECs与免疫反应密切相关。
在本研究中，设计了靶向并修复ECs的P-选择素结合肽-细胞外囊泡（PBP-EVs）。转录组测序显示，PBP-EVs可降低AKI小鼠中炎症基因的表达。使用高分辨率活体双光子显微镜（TPM），观察到PBP-EVs处理后AKI Foxp3-EGFP转基因小鼠肾脏中Tregs的募集增加，以及AKI Lgr5-Cre; R26小鼠中Lgr5肾干细胞的显著增殖。此外，PBP-EVs处理可减少AKI小鼠炎症细胞的浸润、病理损伤和纤维化。在Foxp3-DTR转基因小鼠中耗竭Tregs后，我们观察到PBP-EVs对AKI的治疗效果减弱。
实验结果表明，PBP-EVs可通过减轻内皮细胞损伤，进而调节Tregs和免疫微环境，促进AKI的修复和再生。这些发现为AKI的治疗提供了新的见解和策略。
