Urinary citrate is an inhibitor of nephrolithiasis and nephrocalcinosis. It complexes with urinary calcium, preventing the calcium from forming insoluble complexes with oxalate. The rate of citrate excretion is determined by the rate of proximal tubule citrate reabsorption and metabolism. Citrate is transported across the proximal tubule apical and basolateral membranes by Na-coupled, electrogenic transporters. NaDC-1 mediates citrate reabsorption across the apical membrane, which is stimulated by acidic pHs, and succinate reabsorption, which is not affected by pH. NaDC-3 likely mediates citrate and succinate uptake across the basolateral membrane. However, unlike transport across the apical membrane, both succinate and citrate transport are inhibited by acidic pHs. Thus, acidic pHs inhibit NaDC-3, but not NaDC-1 transporter function. The basis for the differences in the direct effects of pH is not known. Urinary citrate excretion is decreased with chronic acid feeding, in potassium deficiency, and with increases in animal protein intake. We have shown that it is the acid load, and likely the intracellular acidosis common to these conditions, that correlates with the increase in citrate reabsorption and decrease in citrate excretion. The mechanisms by which pH signals these chronic adaptations are unknown. There are 3 aims.
Aim 1 will define the mechanisms and domains of the NaDC-1 protein that confer its characteristic pH profile by identifying the NaDC-1 domain that prevents the acid-induced inhibition of transporter function, determining the sidedness of the direct pH effect, and identifying the protein region and mechanism by which citrate transport is increased at acid pHs. Since NaDC-1 and NaDC-3 have widely disparate characteristics, we will use a domain swapping approach, followed by more refined mutagenesis experiments to localize the pH regulatory elements in the transport protein.
Aim 2 will define the adaptive mechanism(s) that mediate the increase in citrate reabsorption with increases in animal protein intake, and determine if the same mechanisms are involved in the regulation of citrate reabsorption in chronic metabolic acidosis and potassium deficiency.
Aim 3 will elucidate the acid-activated signaling pathway that mediates the chronic regulation of citrate reabsorption. At the completion of these studies we will have identified the NaDC-1 amino acid domains that give it it's I characteristic pH profile and established a model for the chronic adaptations that regulate citrate reabsorption.
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