Adriamycin nephropathy induces sensorineural hearing loss via blood-labyrinth barrier breakdown in BALB/c mice.

Sensorineural hearing loss (SNHL) is significantly more prevalent in individuals with chronic kidney disease (CKD) than in the general population. Although a strong independent association has been observed between kidney dysfunction and the risk of hearing loss, the underlying mechanisms linking these conditions remain poorly understood. This study investigated the pathophysiology of hearing impairment using adriamycin nephropathy (AN), a well-established animal model of CKD. AN was induced in male BALB/c mice using 10 or 12 mg/kg of adriamycin (ADR), resulting in severe kidney injury and concurrent hearing loss. ADR-treated mice exhibited significant glomerular injury, podocyte damage, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL), along with increased serum creatinine and blood urea nitrogen levels. Hearing impairment was evident after 4-8 weeks of ADR treatment, as assessed by auditory brainstem response and distortion-product otoacoustic emissions, and was accompanied by cochlear hair cell loss and ribbon synapse degeneration. AN affected cochlear function by altering ion channel expression in the stria vascularis and inducing blood-labyrinth barrier (BLB) hyperpermeability, along with changes in endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes. AN significantly increased cochlear NGAL and NLRP3 levels at 4 and 8 weeks following ADR administration. NGAL was highly expressed in the tectorial membrane, cochlear neurons, and organ of Corti, while its receptor, 24p3R, was co-localized with NGAL. These findings demonstrated the role of NGAL and BLB disruption in ADR-induced SNHL, providing novel insights into the mechanistic link between CKD and hearing loss.