Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China.
Department of Nephrology, the Second Xiangya Hospital of Central South University, Changsha, China.
Biochem Pharmacol. 2024 Nov;229:116505. doi: 10.1016/j.bcp.2024.116505. Epub 2024 Aug 23.
Chronic Kidney Disease (CKD) is a significant global health issue linked to dietary habits, especially high salt intake. However, the precise mechanisms driving this progression remain incompletely understood. This study reveals that a high-salt diet intensifies macrophage trained immunity, leading to a marked pro-inflammatory response upon repeated pathogenic exposures, as evidenced by increased renal damage and fibrosis. Under high-salt conditions, there was an induction of CD45F4/80 macrophage infiltration into the renal tissue, accompanied by heightened production of inflammatory cytokines. Distinct responses were observed between circulating and resident renal macrophages to a high-salt diet, with a notable upsurge in the migration of pro-inflammatory macrophages, driven by CCL2-CCR2 signaling and aberrant mTORC1 pathway activation. Treatment with rapamycin-liposome effectively reduced this inflammatory cascade by mitigating mTORC1 signaling. Transplantation of monocytes from CKD mice with a high-salt diet significantly exacerbates renal inflammatory damage in the host mice, showing increased migratory tendency and inflammatory activity. The cell co-culture experiment further confirmed that macrophages derived from CKD mice, particularly those under conditions of high salt exposure, significantly induced apoptosis and inflammatory responses in renal tubular cells. Taken together, recurrent exposure to LPS elicits the activation of trained immunity, consequently augmenting inflammatory response of monocytes/macrophages in the involved kidneys. The high-salt diet exacerbates this phenomenon, attributable at least in part to the overactivation of the mTORC1 pathway. This research emphasizes the importance of dietary modulation and targeted immunological interventions in slowing CKD progression, providing new insights into mTORC1-mediated pathophysiological mechanisms and potential management strategies for CKD.
慢性肾脏病（CKD）是一个重大的全球健康问题，与饮食习惯有关，尤其是高盐摄入。然而，导致这种进展的确切机制仍不完全清楚。本研究揭示，高盐饮食加剧了巨噬细胞的训练免疫，导致在反复接触病原体时产生明显的促炎反应，表现为肾脏损伤和纤维化的显著增加。在高盐条件下，CD45F4/80 巨噬细胞浸润到肾组织中，并伴有炎症细胞因子的产生增加。在高盐饮食下，循环和固有肾巨噬细胞之间观察到不同的反应，促炎巨噬细胞的迁移明显增加，这是由 CCL2-CCR2 信号和异常 mTORC1 途径激活所驱动的。雷帕霉素脂质体治疗通过减轻 mTORC1 信号显著降低了这种炎症级联反应。从高盐饮食的 CKD 小鼠中移植单核细胞，显著加重了宿主小鼠的肾脏炎症损伤，表现出更高的迁移倾向和炎症活性。细胞共培养实验进一步证实，源自 CKD 小鼠的巨噬细胞，特别是在高盐暴露条件下的巨噬细胞，可显著诱导肾脏肾小管细胞的凋亡和炎症反应。总之，反复暴露于 LPS 会引发训练免疫的激活，从而增强受累肾脏中单核细胞/巨噬细胞的炎症反应。高盐饮食加剧了这种现象，至少部分归因于 mTORC1 途径的过度激活。这项研究强调了饮食调节和靶向免疫干预在减缓 CKD 进展中的重要性，为 mTORC1 介导的病理生理机制和 CKD 的潜在管理策略提供了新的见解。
