β2-Microglobulin, interleukin-31, and arachidonic acid metabolites (leukotriene B₄ and thromboxane A₂) are involved in chronic renal failure-associated itch-associated responses in mice

Chronic renal failure (CRF) is a progressive disease with severe pruritus and dry skin as the major symptoms. However, the mechanisms of CRF-induced pruritus remain unclear. In this study, 5/6 nephrectomized (NPCT) mice were used as a mouse model of CRF. Serum concentrations of blood urea nitrogen and creatinine in 5/6 NPCT mice were increased. The stratum corneum water content in the skin of 5/6 NPCT mice was decreased. These findings suggest that 5/6 nephrectomy in mice results in a phenotype resembling human CRF. 5/6 NPCT mice showed spontaneous scratching, which was inhibited by μ-opioid receptor antagonist, suggesting that the scratching is an itch-related response. The number of cutaneous mast cells was not altered in 5/6 NPCT mice compared with sham-operated mice. The H₁ histamine-receptor antagonist, proteinase-activated receptor 2-neutralizing antibody, and 5-HT₃-receptor antagonist did not inhibit spontaneous scratching in 5/6 NPCT mice; therefore, the role of mast cells and serotonin in spontaneous scratching appears to be minimal. The anti-allergy agent azelastine, BLT leukotriene (LT) B₄ receptor antagonist, and TP thromboxane (TX) A₂ receptor antagonist inhibited spontaneous scratching in 5/6 NPCT mice, suggesting that LTB₄ and TXA₂ are involved in CRF-induced pruritus. Interestingly, in the skin of 5/6 NPCT mice, levels of two newly identified pruritogens (β2-microglobulin and interleukin-31) were increased. Taken together, these findings suggest that 5/6 NPCT mice are useful for the study of itching in CRF. In addition to LTB₄ and TXA₂, it is also suggested that β2-microglobulin and interleukin-31 are involved in itching associated with CRF-induced pruritus.