​​​​MAST CELL–MICROGLIA AXIS DRIVES COGNITIVE IMPAIRMENT AND PERIPHERAL NEUROPATHY IN EXPERIMENTAL CHRONIC KIDNEY DISEASE

Chronic kidney disease (CKD) frequently induces cognitive deficits and peripheral neuropathy in stages IV–V, yet underlying mechanisms remain elusive. Here, we elucidate the role of mast cell–microglia interactions triggering neuroinflammation via tryptase and pro-inflammatory mediators, impairing neuronal function. Adult female C57BL/6 mice received adenine (0.1% w/v) to induce CKD, alongside healthy control, vehicle (saline), or sodium cromolyn (SCG; 3.15 mg/kg, i.p.). Behavioural tests assessed cognitive function and neuropathic pain. Mice were euthanized for Western blot, histological, and biochemical analyses of hippocampus and sciatic nerve. N9 microglial cells were exposed to serum from control, CKD, or SCG-treated groups, followed by Western blot and immunocytochemistry for pro-inflammatory cytokines. SCG improved recognition memory (novel object recognition), emotional memory (passive avoidance test), mechanical/thermal hyperalgesia (pin-prick/hot-plate test), anxiety/depressive-like behaviour (open-field/tail-suspension), and motor function (Rota-rod), compound muscle action potential (CMAP) in motor nerve conduction study without affecting renal function. Toluidine blue staining revealed significantly fewer mast cells in the hippocampus and sciatic nerve of SCG-treated mice. Western blot and immunofluorescence confirmed reduced tryptase expression in the SCG group. Molecular analyses showed SCG upregulated memory markers (BDNF, p-CREB, CAMKII, PSD-95; not CREB) while downregulating pro-inflammatory markers (TNF-α, IL-6). In N9 cells exposed to SCG serum and hippocampal sections, IBA-1+ cells were also found to be downregulated, alongside reduced IL-6 and TNF-α versus CKD group. Thus, findings demonstrate that targeting the mast cell–microglia axis with SCG ameliorates CKD-associated cognitive impairment and neuropathic pain by inhibiting tryptase-driven microglial activation and neuroinflammation.