Sustained bone marrow myeloid-skewing is associated with systemic inflammation in adenine-induced chronic kidney disease mice 2258869

Abstract

Abstract Introduction Chronic kidney disease (CKD), affecting over 10% of the global population, is frequently accompanied by comorbidities such as cardiovascular disease (CVD), largely driven by chronic inflammation. Emerging evidence implicates trained immunity, a form of innate immune memory triggered by uremic toxins, in sustaining inflammatory responses in CKD. However, its physiological relevance remains unvalidated in appropriate animal models. Methods CKD was induced in C57BL/6 mice using a 0.2% adenine-containing diet administered for 2 or 4 weeks, followed by a resting phase to assess the development of trained immunity. Serum creatinine (Cr) and blood urea nitrogen (BUN) were measured to evaluate renal function, while histopathological changes were examined via Hematoxylin & Eosin (H&E) and Masson’s trichrome (M-T) staining. Flow cytometry of spleen and bone marrow was performed for immunophenotyping, and systemic cytokine responses were analyzed after intraperitoneal lipopolysaccharide (LPS; 5 mg/kg) challenge using ELISA. Results Adenine-fed mice showed significantly elevated serum Cr and BUN levels, with tubular injury and interstitial fibrosis that worsened with prolonged adenine exposure, confirming CKD establishment. Partial recovery of renal parameters and histopathology occurred following the resting period. Nevertheless, flow cytometric analysis revealed a sustained expansion of myeloid-biased multipotent progenitor cells (MPP3) in bone marrow, persisting beyond renal recovery. Upon secondary LPS stimulation, previously adenine-fed mice produced markedly higher serum levels of TNF-α and IL-6, characteristic of a trained immunity phenotype. Conclusion These findings demonstrate that adenine-induced CKD leads to long-term reprogramming of hematopoietic progenitor cells, promoting an enhanced inflammatory response that may contribute to persistent inflammation and the progression of CKD-associated CVD. Funding Source This work was supported in part by grants (RS-2022-NR070612 and RS-2022-NR070765 to W-W. Lee) from the National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (MSIT) and by a grant (RS-2023-00238632 to H.Y.K.) of Basic Science Research Program through NRF funded by the Ministry of Education, Republic of Korea. Topic Categories Hematopoiesis and Immune System Development (HEM)