Li Chenyang, Wang Shuai, Liao Chenghui, Li Ying, Zhou Yunfeng, Wu Haiqiang, Xiong Wei
School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
Biomater Res. 2024 Oct 24;28:0099. doi: 10.34133/bmr.0099. eCollection 2024.
Klotho (KLO) is an anti-fibrotic protein expressed in the kidneys and has been decreasing in the development of renal fibrosis (RF). However, restoring the decline in KLO levels remains a great challenge during RF treatment. Herein, an injectable KLO-loaded chitosan (CS) hydrogel (KLO-Gel) is designed to achieve localized and prolonged release of KLO in the RF treatment. KLO-Gel was prepared by cross-linking CS with β-glycerophosphate (β-GP), followed by rapid (within 3 min) thermosensitive gelation at 37 °C. Furthermore, KLO-Gel exhibited a slow and sustained release (over 14 d) of KLO both in PBS and in the kidneys of mice with unilateral ureter obstruction (UUO). A single local injection of KLO-Gel into the renal capsule of UUO mice was more effective at reducing RF (i.e., maintaining renal function and tissue structure, alleviating extracellular matrix accumulation, and inhibiting the TGF-β1/Smad2/3 signaling pathway) over a 14-d period than daily intraperitoneal injections of free KLO or captopril. Crucially, CS was found to induce endogenous KLO secretion, highlighting the added value of using CS in RF treatment. Overall, this study demonstrated that KLO-Gel enhanced the anti-fibrotic efficacy of KLO while minimizing its off-target toxicity, and its clinical potential awaits further validation.
klotho（KLO）是一种在肾脏中表达的抗纤维化蛋白，在肾纤维化（RF）发展过程中其表达量不断下降。然而，在RF治疗过程中恢复KLO水平的下降仍然是一个巨大的挑战。在此，设计了一种可注射的负载KLO的壳聚糖（CS）水凝胶（KLO-Gel），以在RF治疗中实现KLO的局部和长效释放。KLO-Gel是通过将CS与β-甘油磷酸酯（β-GP）交联制备的，随后在37℃下快速（3分钟内）发生热敏凝胶化。此外，KLO-Gel在PBS和单侧输尿管梗阻（UUO）小鼠的肾脏中均表现出KLO的缓慢且持续释放（超过14天）。在14天的时间里，单次局部注射KLO-Gel到UUO小鼠的肾包膜中，在减轻RF方面（即维持肾功能和组织结构、减轻细胞外基质积聚以及抑制TGF-β1/Smad2/3信号通路）比每日腹腔注射游离KLO或卡托普利更有效。至关重要的是，发现CS可诱导内源性KLO分泌，突出了在RF治疗中使用CS的附加价值。总体而言，本研究表明KLO-Gel增强了KLO的抗纤维化功效，同时将其脱靶毒性降至最低，其临床潜力有待进一步验证。
