Despite its obvious importance for understanding drug handling in neonates and children, little is known about the development and maturation the renal proximal tubule and its capacity for xenobiotic handling, which is mediated by an organic anion transport pathway. Although organic anionic drug transport capacity varies considerably with age, information about the developmental regulation of the specific gene products mediating organic anion transport is scant. Recently many of the organic anion transporters (OATs) have been identified. We were the first to clone and characterize expression of the basolateral renal OAT (NKT/OAT1), which appears to be extremely important in drug handling. NKT/OAT1 is part of a family of homologous genes which includes NLT/OAT2, Roct and other genes. The plethora of genes involved suggests that the renal organic anion transport system is much more complex than originally thought. Moreover, all OATS we have examined exhibit roughly the same spatiotemporal expression pattern in the developing proximal tubule, suggesting coordinate regulation.
Its aims are to: 1) investigate the developmental expression and mechanisms of regulation of the OATs during proximal tubulogenesis in the developing kidney and during postnatal maturation (embryonic kidney organ culture, Northern analysis, in situ hybridization, RT-PCR, immunohistochemistry). 2) fully analyze the developmental and functional consequences for organic anion transport in a Roct knockout animal and to develop an OAT1 knock-out animal, as well as a hybid Roct/OAT1 knockout mouse (measurement of organic anion levels in plasma and urine, Northern analysis to analyze expression of other OATs that may potentially compensate for the defect in embryonic, neonatal and adult mice, microarray technology). Considerable new data and new methodological information is presented to address issues raised in the first review. New key personnel have been added to strengthen the team, which has specific expertise in the molecular biology and physiology of OATs, transcriptional regulation, creation of knockouts and their analysis. Together, these studies should provide key insights not only into the development and maturation of renal drug handling capacity but also into mechanisms of proximal tubulogenesis.
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