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. 2025 May 18.
doi: 10.1007/s10157-025-02697-6. Online ahead of print.

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

Huili Li  1 , Weiwei Gao  1 , Xiue Mu  1 , Liang Du  2
Affiliations

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

Huili Li et al. Clin Exp Nephrol. .

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 (LCN2-/- mice) 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.

Keywords: Chemokine; GRP/GRPR; LCN2; Morphine-induced pruritus; Pro-inflammatory cytokine; Uremic pruritus.

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Conflict of interest statement

Declarations. Competing interest: No. Ethical approval: The human protocol was approved by the Joint Ethics Committee of the Ministry of Health under Approval No- HMU2024_789321 while animal protocol for both models were approved by Hebei Medical University under ethical approval HMU_2024-56990310. Consent to participate: Not applicable. Consent to publish: Not applicable.

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