Does membrane trafficking play a role in regulating the sodium/hydrogen exchanger isoform 3 in the proximal tubule?

The proximal tubule sodium/hydrogen exchanger continuously reabsorbs the bulk of the filtered sodium, controlling salt delivery to the distal nephron which is critical for tubuloglomerular feedback autoregulation and for fine control of salt excretion in the distal nephron. This review focuses on recent studies of the mechanisms of regulation of sodium transport in the proximal tubule, and addresses whether results from studies in proximal tubule cell lines are applicable to the proximal tubule in situ. Recent in-vivo studies provided evidence that sodium/hydrogen exchanger isoform 3 can move into and out of the apical microvilli accompanied by parallel changes in renal sodium transport: the exchanger is retracted from the microvilli in response to hypertension, parathyroid hormone or dopamine treatment and moved into the microvilli in response to sympathetic nervous system stimulation, puromycin aminonucleoside induced nephritic syndrome, and insulin treatment. Studies in cultured opossum kidney proximal tubule cells provided evidence for clathrin coated vesicle mediated, dynamin dependent, cytoskeleton dependent internalization of sodium/hydrogen exchanger isoform 3 from the surface to an endosomal pool in response to dopamine or parathyroid hormone. In the intact proximal tubule there is evidence for a two-step internalization process: (1) from villi to the intermicrovillar cleft region and (2) to a higher density membrane pool that may be either below the microvilli or deep in intermicrovillar clefts. Recent studies have described a significant inactive pool of the exchanger in the intermicrovillar region in vivo that may serve as a storage and recruitable pool. The molecular mechanisms responsible for increasing or decreasing sodium transport in the proximal tubule appear to include redistribution of sodium/hydrogen exchanger isoform 3 to or from the microvillar region. Detailed studies in cultured proximal tubule cell lines provide evidence for endocytosis and exocytosis of the exchanger dependent on cytoskeleton and clathrin coated vesicles. In vivo, the apical membrane is differentiated into discrete villar and intermicrovillar membrane domains and the intermicrovillar domain, not observed in cultured cells, may serve as a recruitable storage pool for sodium/hydrogen exchanger isoform 3.