Zheng Haofeng, Zhang Yannan, Li Lei, Zhang Rui, Luo Zihuan, Yang Zhe, Ye Yongrong, He Jiannan, Sun Qiquan
Organ Transplantation Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Front Cell Dev Biol. 2021 Feb 12;9:641527. doi: 10.3389/fcell.2021.641527. eCollection 2021.
Toll-like receptor-9 (TLR-9) is a potent proinflammatory receptor that mediates renal injury. However, the reported effects of TLR-9 are contradictory. Here, using a traditional mouse AKI→CKD transition model, the roles of TLR-9 during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) were further explored. Using a TLR-9 mouse, the effects and mechanisms of TLR-9 were investigated. Loss of TLR-9 elicited no obvious effects as regards renal function or histology during AKI in the early phases (24-48 h), while TLR-9 KO attenuated renal fibrosis (as shown using fibronectin and collagen III) and epithelial-to-mesenchymal transition (EMT) [E-cadherin (E-Cad) and α-smooth muscle actin (α-SMA)] on the long-term after AKI through the inhibition of macrophages infiltration, especially M2 macrophages. The roles of TLR-9 on macrophages were also explored using Raw264.7 macrophage cell line, and results indicated that the inhibition of TLR-9 on Raw 264.7 macrophages decreased the induction of M2 type macrophage in a dose-dependent manner. The roles of TLR-9 on renal tubular epithelial (RTE) cells were also explored. Conversely, TLR-9 depletion did not contribute to the improvement of fibrosis and EMT . Therefore, TLR-9 plays a critical role in the AKI→CKD transition. Attenuation of CKD post-AKI in the TLR-9 KO group mainly relies on the effects of TLR-9 on macrophages. These results also suggest that TLR-9 could be a therapeutic target for CKD.
Toll样受体9（TLR-9）是一种介导肾损伤的强效促炎受体。然而，关于TLR-9的报道效应相互矛盾。在此，利用传统的小鼠急性肾损伤（AKI）向慢性肾病（CKD）转变模型，进一步探究了TLR-9在从急性肾损伤（AKI）转变为慢性肾病（CKD）过程中的作用。使用TLR-9基因敲除小鼠，研究了TLR-9的作用及机制。在早期急性肾损伤阶段（24 - 48小时），TLR-9缺失对肾功能或组织学无明显影响，而TLR-9基因敲除通过抑制巨噬细胞浸润，尤其是M2巨噬细胞，在急性肾损伤后的长期过程中减轻了肾纤维化（如使用纤连蛋白和III型胶原所示）以及上皮-间质转化（EMT）[E-钙黏蛋白（E-Cad）和α-平滑肌肌动蛋白（α-SMA）]。还使用Raw264.7巨噬细胞系探究了TLR-9对巨噬细胞的作用，结果表明抑制TLR-9对Raw 264.7巨噬细胞的作用可剂量依赖性地减少M2型巨噬细胞的诱导。也探究了TLR-9对肾小管上皮（RTE）细胞的作用。相反，TLR-9缺失无助于纤维化和上皮-间质转化的改善。因此，TLR-9在急性肾损伤向慢性肾病的转变中起关键作用。TLR-9基因敲除组急性肾损伤后慢性肾病的减轻主要依赖于TLR-9对巨噬细胞的作用。这些结果还表明TLR-9可能是慢性肾病的治疗靶点。
