Astrocytic LCN2 drives uremic pruritus and morphine-induced pruritus via the GRP/GRPR pathway.

Abstract

BACKGROUND: Uremic pruritus (UP) is a distressing condition in hemodialysis patients with unclear mechanisms. This study investigates the role of LCN2 in pruritus, focusing on its interaction with GRP/GRPR signaling and astrocyte activation. METHODS: Clinical skin biopsy samples from CKD patients with and without UP were analyzed for LCN2 expression. A chronic renal failure mouse model (UP model) was established through surgical kidney ablation, while a morphine-induced itch model was generated via intrathecal morphine injection. LCN2 knockout (LCN2) mice were used to evaluate its functional role in itch modulation. Scratching behavior was recorded, and Western blot, qRT-PCR, immunohistochemistry, immunofluorescence, and ELISA were performed to assess LCN2 expression, GRP/GRPR signaling, and inflammatory cytokines in the spinal cord. Additionally, RC-3095 (a GRPR inhibitor) and GRP were administered to evaluate their effects on pruritus. RESULTS: LCN2 expression was elevated in CKD patients with UP and positively correlated with itch severity. Similarly, UP model mice showed increased spinal LCN2 levels, while LCN2 deficiency (LCN2mice) reduced scratching behavior. Mechanistically, LCN2 promoted pruritus by enhancing GRP/GRPR signaling and astrocyte activation. Blocking GRP/GRPR with RC-3095 reduced pruritus in both UP and morphine-induced models, confirming LCN2's role in itch transmission. CONCLUSION: LCN2 mediates pruritus by promoting GRP/GRPR signaling, astrocyte activation, and neuroinflammation, making it a potential therapeutic target for CKD-related and opioid-induced pruritus.