Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Nephrology, Xiaogan Central Hospital, Xiaogan, Hubei, China.
Int J Biol Sci. 2022 Jan 1;18(3):1171-1187. doi: 10.7150/ijbs.66781. eCollection 2022.
Renal lymphangiogenesis is a new field of international nephrology in recent years and plays an important role in the progression of chronic renal disease. CD137 was originally described as a surface molecule present on activated T and NK cells and detected on hypoxic endothelial cells and inflamed blood vessels, but its function on lymphatic endothelial cells remains unclear. We investigated the relationships among CD137, lymphangiogenesis and macrophages, which are involved in interstitial fibrosis. Similar to other chronic inflammatory diseases, we found lymphangiogenesis and expression of CD137 in the renal tissue of patients with IgA nephropathy. CD137-positive lymphatic vessels were involved in the development process of IgA nephropathy and positively correlated with serum creatinine, serum urea nitrogen, serum uric acid, and urinary 24 h total protein. The expression of these indicators was negatively correlated with eGFR, plasma albumin, and HB. In mouse models of UUO, we verified that CD137 expression was significantly elevated during lymphangiogenesis and that its ligand CD137L was released by macrophages after VEGF-C stimulation in the kidney. In vitro, recombinant CD137L significantly enhanced LEC proliferation, migration and tube formation, and these effects were inhibited by CD137 siRNA. Mechanistically, the CD137L interaction with CD137 induced the transition from LC3-I to LC3-II and the expression of Atg5, Atg7, Atg12 and p62 proteins by activating the PI3K/AKT/mTOR pathway to promote autophagy. Knockdown of Atg5 and Atg7 blocked CD137L-induced autophagy. Thus, we propose that CD137L secretion by macrophages interacts with CD137 on lymphatic endothelial cells to prompt lymphangiogenesis in the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the CD137-CD137L pathway is a novel therapeutic approach for obstructive nephropathy.
肾淋巴管生成是近年来国际肾脏病学的一个新领域，在慢性肾脏病的进展中起着重要作用。CD137 最初被描述为存在于活化的 T 和 NK 细胞表面的分子，并在缺氧的内皮细胞和炎症血管中检测到，但它在淋巴管内皮细胞上的功能尚不清楚。我们研究了 CD137、淋巴管生成和参与间质纤维化的巨噬细胞之间的关系。与其他慢性炎症性疾病类似，我们发现 IgA 肾病患者的肾组织中存在淋巴管生成和 CD137 的表达。CD137 阳性淋巴管参与 IgA 肾病的发展过程，与血清肌酐、血清尿素氮、血清尿酸和尿 24 小时总蛋白呈正相关。这些指标的表达与 eGFR、血浆白蛋白和 HB 呈负相关。在 UUO 小鼠模型中，我们验证了 CD137 表达在淋巴管生成过程中显著升高，其配体 CD137L 在肾脏中 VEGF-C 刺激后由巨噬细胞释放。在体外，重组 CD137L 显著增强 LEC 的增殖、迁移和管形成，而这些作用被 CD137 siRNA 抑制。在机制上，CD137L 与 CD137 的相互作用通过激活 PI3K/AKT/mTOR 通路诱导 LC3-I 向 LC3-II 的转变以及 Atg5、Atg7、Atg12 和 p62 蛋白的表达，从而促进自噬。Atg5 和 Atg7 的敲低阻断了 CD137L 诱导的自噬。因此，我们提出巨噬细胞分泌的 CD137L 与淋巴管内皮细胞上的 CD137 相互作用，促使肾脏淋巴管生成，进而驱动纤维生成反应。我们的研究结果表明，抑制 CD137-CD137L 通路是治疗梗阻性肾病的一种新的治疗方法。
