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Organic anion and cation transporters (OATs, OCTs and OCTNs) mediate the proximal tubular secretion of numerous clinically important compounds, including various commonly prescribed pharmaceuticals. Here, we examine the ontogeny of these transporters in rat embryonic kidney in detail, both in vivo and in two in vitro organ culture models of kidney development, whole embryonic kidney (WEK) culture and culture of induced metanephric mesenchyme (MM).
We used QPCR to determine expression levels of transporter genes in rat embryonic kidneys on each day of gestation from ed13 to ed18, in induced and un-induced MM, and on each day of one week of WEK culture. We also used uptake of fluorescein as a novel functional assay of organic anion transporter expression in WEK and MM.
The developmental induction of the various organic anion and cation transporter genes does not occur uniformly: some genes are induced early (e.g., Oat1 and Oat3, potential early markers of proximal tubulogenesis), and others not till kidney development is relatively advanced (e.g., Oct1, a potential marker of terminal differentiation). We also find that the ontogeny of transporter genes in WEK and MM is similar to that observed in vivo, indicating that these organ culture systems may appropriately model the expression of OATs, OCTs and OCTNs.
We show that WEK and MM cultures may represent convenient in vitro models for study of the developmental induction of organic anion and cation transporters. Functional organic anion transport as measured by fluorescein uptake was evident by accumulation of the fluorescence in the developing tubule in these organ cultures. By demonstrating the mediated uptake of fluorescein in WEK and MM, we have established a novel in vitro functional assay of transporter function. We find that OATs, OCTs, and OCTNs are differentially expressed during proximal tubule development. Our findings on the renal ontogeny of organic anion and cation transporters could carry implications both for the development of more rational therapeutics for premature infants, as well as for our understanding of proximal tubule differentiation.
Copyright 2006 International Society of Nephrology. This is the author’s manuscript of a work that was accepted for publication in Kidney Int. 2006 Mar; 69(5): 837–845. The final publication is available at http://dx.doi.org/10.1038/sj.ki.5000170
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