Wang Zufeng, Cheng Yichun, Fan Jiahe, Luo Ran, Xu Gang, Ge Shuwang
Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Road, Wuhan, 430030, China.
Mol Med. 2024 Dec 20;30(1):254. doi: 10.1186/s10020-024-01026-z.
Recent data has shown a considerable advancement in understanding the role of lymphotoxin-β receptor (LTβR) in inflammation. However, the functions and underlying mechanisms of LTβR in acute kidney injury (AKI) remain largely unknown.
AKI was induced in mice by renal ischemia-reperfusion (I/R). HK-2 cells and primary renal tubular epithelial cells (RTECs) were subjected to hypoxia/reoxygenation (H/R) injury. The effects of LTβR depletion were examined in mice, as well as primary RTECs. Bone marrow chimeric mice was generated to determine whether the involvement of LTβR expression by parenchymal cells or bone marrow derived cells contributes to renal injury during AKI. RNA sequencing techniques were employed to investigate the mechanism via which LTβR signaling provides protection against I/R-induced AKI RESULTS: LTβR expression was downregulated both in vivo and in vitro models of AKI. Moreover, depletion of LTβR decreased renal damage and inflammation in I/R-induced AKI. We also found that LTβR deficient mice engrafted with wild type bone marrow had significantly less tubular damage, implying that LTβR in renal parenchymal cells may play dominant role in I/R-induced AKI. RNA sequencing indicated that the protective effect of LTβR deletion was associated with activation of PPARα signaling. Furthermore, upregulation of PPARα was observed upon depletion of LTβR. PPARα inhibitor, GW6471, aggravated the tubular damage and inflammation in LTβR mice following I/R injury. Then we further demonstrated that LTβR depletion down-regulated non-canonical NF-κB and Bax/Bcl-2 apoptosis pathway through PPARα.
Our results suggested that the LTβR/PPARα axis may be a potential therapeutic target for the treatment of AKI.
最近的数据表明，在理解淋巴毒素-β受体（LTβR）在炎症中的作用方面取得了相当大的进展。然而，LTβR在急性肾损伤（AKI）中的功能和潜在机制仍 largely未知。
通过肾脏缺血再灌注（I/R）在小鼠中诱导AKI。HK-2细胞和原代肾小管上皮细胞（RTECs）遭受缺氧/复氧（H/R）损伤。在小鼠以及原代RTECs中检测LTβR缺失的影响。生成骨髓嵌合小鼠以确定实质细胞或骨髓来源细胞中LTβR表达的参与是否有助于AKI期间的肾损伤。采用RNA测序技术研究LTβR信号传导提供针对I/R诱导的AKI的保护作用的机制。结果：在AKI的体内和体外模型中，LTβR表达均下调。此外，LTβR的缺失减少了I/R诱导的AKI中的肾损伤和炎症。我们还发现，移植有野生型骨髓的LTβR缺陷小鼠的肾小管损伤明显更少，这意味着肾实质细胞中的LTβR可能在I/R诱导的AKI中起主导作用。RNA测序表明，LTβR缺失的保护作用与PPARα信号传导的激活有关。此外，在LTβR缺失后观察到PPARα上调。PPARα抑制剂GW6471加重了I/R损伤后LTβR小鼠的肾小管损伤和炎症。然后我们进一步证明，LTβR缺失通过PPARα下调非经典NF-κB和Bax/Bcl-2凋亡途径。
我们的结果表明，LTβR/PPARα轴可能是治疗AKI的潜在治疗靶点。
