Dietary Sodium Modulates mTORC1-Dependent Trained Immunity in Macrophages to Accelerate AKI to CKD Transition

Background: Chronic Kidney Disease (CKD) constitutes a substantial global health concern, with its etiology closely associated with dietary patterns, particularly elevated salt consumption, and recurrent infections that precipitate the transition from Acute Kidney Injury (AKI) to CKD. However, the mechanistic pathways underpinning this progression have yet to be fully elucidated. Methods: Flow cytometry，RT PCR，ELISA，Western blot analysis, renal histological analysis, immunofluorescent and immunohistochemical staining were performed to measure the inflammatory response of macrophages in AKI to CKD and how high-salt diet aggravates this response by modulating mTORC1 pathway. Results: Analysis shows elevated CD45+F4/80+ macrophage infiltration and inflammatory cytokine production under high-salt conditions. 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. Conclusion: 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. Funding: Government Support – Non-U.S.