Elevated asymmetric dimethylarginine drives hematopoietic stem cell metabolic reprogramming and dysfunction in chronic kidney disease.

Chronic kidney disease (CKD) is commonly linked to hematopoietic abnormalities beyond the well-recognized anemia, with underlying mechanisms poorly understood. Here, we show that asymmetric dimethylarginine (ADMA), which accumulates in the CKD microenvironment, perturbs hematopoietic stem cell (HSC) homeostasis. Clinical data analysis reveals that serum ADMA levels rise with CKD progression and inversely correlate with the myeloid-to-lymphoid ratio. Notably, ADMA compromises HSC quiescence and long-term repopulating capacity, as observed in CKD mouse models established by 5/6 nephrectomy. Further investigations demonstrate that ADMA hyperactivates mammalian target of rapamycin (mTOR) signaling, promoting the transition from glycolysis to oxidative phosphorylation and inducing reactive oxygen species (ROS) overproduction in HSCs. Mechanistically, ADMA binds with high affinity to protein phosphatase 2 regulatory subunit Bβ (PPP2R2B), relieving its inhibition of mTOR signaling. Inhibition of mTOR signaling by rapamycin or clearance of ROS by NAC reverses ADMA-induced HSC functional defects. Collectively, our findings identify ADMA as a key mediator of CKD-associated hematopoietic dysfunction via the PPP2R2B-mTOR-mitochondria axis, providing a potential therapeutic target.