Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
Clin Exp Nephrol. 2024 Jun;28(6):505-512. doi: 10.1007/s10157-024-02494-7. Epub 2024 Apr 17.
Inflammation plays a crucial role in the pathophysiology of various kidney diseases. Kidney perivascular cells (pericytes/fibroblasts) are responsible for producing proinflammatory molecules, promoting immune cell infiltration, and enhancing inflammation. Vascular adhesion protein-1, expressed in kidney perivascular cells, is an ectoenzyme that catalyzes the oxidative deamination of primary amines with the production of hydrogen peroxide in the extracellular space. Our study demonstrated that blocking this enzyme suppressed hydrogen peroxide production and neutrophil infiltration, thereby reducing renal ischemia-reperfusion injury. Sphingosine 1-phosphate (S1P) signaling was also observed to play an essential role in the regulation of perivascular inflammation. S1P, which is produced in kidney perivascular cells, is transported into the extracellular space via spinster homolog 2, and then binds to S1P receptor-1 expressed in perivascular cells. Upon injury, inflammatory signaling in perivascular cells is enhanced by this pathway, thereby promoting immune cell infiltration and subsequent fibrosis. Furthermore, inhibition of S1P transport by spinster homolog 2 reduces kidney fibrosis. Hypoxia-inducible factor-prolyl hydroxylase inhibitors can restore the capacity for erythropoietin production in kidney perivascular cells. Animal data suggested that these drugs could also alleviate kidney and lipid inflammation although the precise mechanism is still unknown. Neuroimmune interactions have been attracting significant attention due to their potential to benefit patients with inflammatory diseases. Vagus nerve stimulation is one of the most promising strategies for harnessing neuroimmune interactions and attenuating inflammation associated with various diseases, including kidney disease. Using cutting-edge tools, the vagal afferents-C1 neurons-sympathetic nervous system-splenic nerve-spleen-kidney axis responsible for kidney protection induced by vagus nerve stimulation was identified in our study. Further research is required to decipher other crucial systems that control kidney inflammation and to determine whether these novel strategies can be applied to patients with kidney disease.
炎症在各种肾脏疾病的病理生理学中起着至关重要的作用。肾脏血管周围细胞（周细胞/成纤维细胞）负责产生促炎分子，促进免疫细胞浸润，并增强炎症反应。血管黏附蛋白-1（Vascular adhesion protein-1，VAP-1）在肾脏血管周围细胞中表达，是一种外酶，能够在细胞外空间中催化伯胺的氧化脱氨作用，产生过氧化氢。我们的研究表明，阻断这种酶可抑制过氧化氢的产生和中性粒细胞浸润，从而减轻肾脏缺血再灌注损伤。还观察到鞘氨醇 1-磷酸（Sphingosine 1-phosphate，S1P）信号在调节血管周围炎症中起着重要作用。S1P 在肾脏血管周围细胞中产生，通过 Spns2 转运到细胞外空间，然后与血管周围细胞表达的 S1P 受体-1 结合。在损伤时，这条通路增强了血管周围细胞的炎症信号，从而促进免疫细胞浸润和随后的纤维化。此外，Spns2 抑制 S1P 转运可减少肾脏纤维化。缺氧诱导因子脯氨酰羟化酶抑制剂可恢复肾脏血管周围细胞产生促红细胞生成素的能力。动物数据表明，尽管确切机制仍不清楚，但这些药物还可以减轻肾脏和脂质炎症。神经免疫相互作用因其有可能使炎症性疾病患者受益而引起了广泛关注。迷走神经刺激是利用神经免疫相互作用减轻与各种疾病（包括肾脏疾病）相关的炎症的最有前途的策略之一。在我们的研究中，使用了尖端工具，确定了迷走神经刺激诱导肾脏保护的迷走神经传入纤维-C1 神经元-交感神经系统-脾神经-脾脏-肾脏轴。需要进一步研究以阐明控制肾脏炎症的其他关键系统，并确定这些新策略是否可以应用于肾脏疾病患者。
