Hyperphosphatemia associated with
chronic kidney disease (CKD) not only dysregulates
mineral metabolism and
bone diseases, but also strongly contributes to the progression of
kidney disease itself. We have identified a novel
drug for
hyperphosphatemia, EOS789, that interacts with several
sodium-dependent
phosphate transporters (NaPi-IIb, PiT-1, and PiT-2) known to contribute to intestinal
phosphate absorption. In this study, we investigated whether EOS789 could ameliorate
kidney disease progression in
glomerulonephritis rats. Anti-glomerular basement membrane (GBM)
nephritis was induced in rats by intravenously administering two types of anti-rat GBM
antibodies. We evaluated the effect of EOS789 administered in food admixture on
hyperphosphatemia and
kidney disease progression. In an
anti-GBM nephritis rats, which exhibit a significant increase in serum
phosphate and a decline in renal function, EOS789 dose-dependently improved
hyperphosphatemia and EOS789 at 0.3% food admixture significantly ameliorated kidney dysfunction as shown in the decline of serum
creatinine and BUN. Renal histopathology analysis showed that EOS789 significantly decreased crescent formation in glomeruli. To elucidate the mechanism underlying glomerular
disease progression, human mesangial cells were used. High
phosphate concentration in media significantly increased the expression of
Collagen 1A1, 3A1, and αSMA
mRNA in human mesangial cells and EOS789 dose-dependently suppressed these fibrotic markers. These results indicate that EOS789 prevented glomerular crescent formation caused by mesangial
fibrosis by ameliorating
hyperphosphatemia. In conclusion, EOS789 would not only be useful against
hyperphosphatemia but may also have the potential to relieve mesangial proliferative
glomerulonephritis with crescent formation.