Abstract
A seminal study recently demonstrated that bromide (Br-) has a critical function in the assembly of type IV collagen in basement membrane (BM), and suggested that Br- supplementation has therapeutic potential for BM diseases. Because salts of bromide (KBr and NaBr) have been used as antiepileptic drugs for several decades, repositioning of Br- for BM diseases is probable. However, the effects of Br- on glomerular basement membrane (GBM) disease such as Alport syndrome (AS) and its impact on the kidney are still unknown. In this study, we administered daily for 16 weeks 75 mg/kg or 250 mg/kg (within clinical dosage) NaBr or NaCl (control) via drinking water to 6-week-old AS mice (mouse model of X-linked AS). Treatment with 75 mg/kg NaBr had no effect on AS progression. Surprisingly, compared with 250 mg/kg NaCl, 250 mg/kg NaBr exacerbated the progressive proteinuria and increased the serum creatinine and blood urea nitrogen in AS mice. Histological analysis revealed that glomerular injury, renal inflammation and fibrosis were exacerbated in mice treated with 250 mg/kg NaBr compared with NaCl. The expressions of renal injury markers (Lcn2, Lysozyme), matrix metalloproteinase (Mmp-12), pro-inflammatory cytokines (Il-6, Il-8, Tnf-α, Il-1β) and pro-fibrotic genes (Tgf-β, Col1a1, α-Sma) were also exacerbated by 250 mg/kg NaBr treatment. Notably, the exacerbating effects of Br- were not observed in wild-type mice. These findings suggest that Br- supplementation needs to be carefully evaluated for real positive health benefits and for the absence of adverse side effects especially in GBM diseases such as AS.
Highlights
Twenty-seven trace elements had been previously considered essential for the maintenance of the human body [1]
We found that 250 mg/kg NaBr slightly but statistically decreased the body weight of Alport syndrome (AS) mice (Fig 1B) no statistical difference in food intake was observed among the groups (S1B Fig). 75 and 250 mg/kg NaCl and 75 mg/kg NaBr had no significant differences in proteinuria score
250 mg/kg NaBr exacerbated the progressive proteinuria starting in 14-weekold mice (Fig 1C). 250 mg/kg NaBr significantly elevated the serum creatinine level compared with high dose NaCl in 22-week-old AS mice (Fig 1D)
Summary
Twenty-seven trace elements had been previously considered essential for the maintenance of the human body [1]. Bromide (Br-) was proposed as the 28th essential trace element, and was demonstrated to be critical in the assembly of type IV collagen scaffolds of the basement membrane (BM) [2]. Bromide supplementation exacerbated renal dysfunction in AS mice. R2803 to H.K.) and Alport Syndrome Foundation (ASF), the Pedersen Family, and the Kidney Foundation of Canada. We are grateful to Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan
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