Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis

Proximal renal tubular acidosis associated with ocular abnormalities such a s band keratopathy glaucoma, and cataracts is caused by mutations in the Na +-HCO3- cotransporter (NBC-1). However, the mechanism by which NBC-1 inacti vation leads to such ocular abnormalities remains to be elucidated. By immu nological analysis of human and rat eyes, we demonstrate that both kidney t ype (kNBC-1) and pancreatic type (pNBC-1) transporters are present in the c orneal endothelium, trabecular meshwork, ciliary epithelium, and lens epith elium. In the human lens epithelial (HLE) cells, RT-PCR detected mRNAs of b oth kNBC-1 and pNBC-1. Although a Na+-HCO3- cotransport activity has not be en detect ed in mammalian lens epithelia, cell pH (pH(i)) measurements reve aled the presence of Cl--independent, electrogenic Na+-HCO3- cotransport ac tivity in HLE cells. In addition, up to 80% of amiloride-insensitive pH(i) recovery from acid load in the presence of HCO3-/CO2 was inhibited by adeno virus-mediated transfer of a specific hammerhead ribozyme against NBC-1, co nsistent with a major role of NBC-1 in overall HCO3- transport by the lens epithelium, These results indicate that the normal transport activity of NB C-1 is indispensable not only for the maintenance of corneal and lenticular transparency but also for the regulation of aqueous humor outflow.