Berbamine Attenuates Chronic Kidney Disease-Associated Pruritus by Targeting MRGPRX1/MrgprC11 Signaling

Chronic kidney disease-associated pruritus (CKD-aP) seriously affects the quality of life and currently has no satisfactory treatment. Mas-related G protein-coupled receptor X1 (MRGPRX1) in humans, corresponding to MrgprC11 in rodents, is an itch receptor. Berbamine is an alkaloid that has the effect of relieving pruritus. This study aimed to investigate the role of MRGPRX1/MrgprC11 in CKD-aP and the potential therapeutic effects of berbamine. MrgprC11 knockout (KO-MrgprC11) mice and MRGPRX1 knockout (KO-MRGPRX1) human dorsal root ganglion (DRG) cells were constructed using the CRISPR/Cas9 technology. Mice were fed adenine and injected with calcium phosphate (CaP) to establish the CKD-aP model and were injected with berbamine. DRG cells were exposed to CaP and treated with berbamine. The results showed that MrgprC11 was associated with itch, kidney injury, and inflammation in mice with CKD-aP. Berbamine attenuated itch and kidney injury. Knockout of MrgprC11 further enhanced the role of berbamine, while activation of MrgprC11 using BAM8-22 reversed the role of berbamine. The in vitro experiments showed that MRGPRX1 was related to the sensitivity to CaP and inflammatory response in CaP-induced DRG cells. Berbamine inhibited these cellular behaviors, while knockout of MRGPRX1 further enhanced the role of berbamine in vitro. In conclusion, MRGPRX1/MrgprC11 signaling plays a critical role in CKD-aP by affecting the activation of DRG cells. Berbamine ameliorates CKD-aP by targeting the MRGPRX1/MrgprC11 signaling. These findings provide promising drugs and targets for the treatment of CKD-aP.