This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Various studies estimate that 19?63% of individuals with calcium containing kidney stones have hypocitraturia as a contributing cause. Understanding the mechanisms of the regulation of citrate transport should lead to improved diagnosis of causes of hypocitraturia. Urinary citrate is an important inhibitor of calcium nephrolithiasis and is primarily determined by fractional reabsorption in the proximal tubule. The dicarboxylate transporter (NaDC1) is presumably the main mechanism of apical uptake of filtered citrate along the nephron. The most important physiologic regulator of urinary citrate excretion is acid-base status. Also urinary citrate increases as urinary calcium increases. The proposed studies will address the acute regulation of citrate transport by calcium, and chronic regulation of citrate transport by acid-base perturbations and hypokalemia. Using a newly characterized in vitro model of citrate transport, OK cells studied under particular conditions, citrate and dicarboxylate uptake are sensitive to extracellular calcium. These studies indicate that the OK cell citrate transport system is likely a novel citrate transporter. Recently another cell line of dicarboxylate transport was developed. Human retinal pigmented epithelial cells stably transfected with human NaDC1 (CUBS cells) are responsive to acid-base conditions in vitro and will therefore represent a powerful new model.
The specific aims are: 1. to delineate the calcium sensitive citrate transport process by: demonstrating that the calcium sensitive citrate transport process is a novel transporter, not NaDC1, and determining the cellular mechanisms whereby extracellular calcium alters this citrate transport process. 2. To delineate the mechanisms of chronic regulation of citrate transport by acid-base perturbations and hypokalemia. To achieve this aim, three modes of regulation will be examined: transcriptional (or mRNA stability) regulation, regulation at the protein level, and regulation by trafficking of NaDC1 into and out of the apical membrane from sub-apical vesicles under conditions of metabolic acidosis and hypokalemia.
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