Yang LE, Sandberg MB, Can AD, Pihakaski-Maunsbach K, McDonough AA. Effects of dietary salt on renal Na ϩ transporter subcellular distribution, abundance, and phosphorylation status. Am J Physiol Renal Physiol 295: F1003-F1016, 2008. First published July 23, 2008 doi:10.1152/ajprenal.90235.2008 diet the kidney increases urinary Na ϩ and volume excretion to match intake. We recently reported that HS provokes a redistribution of distal convoluted tubule Na ϩ -Cl Ϫ cotransporter (NCC) from apical to subapical vesicles and decreases NCC abundance. This study aimed to test the hypothesis that the other renal Na ϩ transporters' abundance and or subcellular distribution is decreased by HS diet. Six-week-old Sprague-Dawley rats were fed a normal (NS) 0.4% NaCl diet or a HS 4% NaCl diet for 3 wk or overnight. Kidneys excised from anesthetized rats were fractionated on density gradients or analyzed by microscopy; transporters and associated regulators were detected with specific antibodies. Three-week HS doubled Na ϩ /H ϩ exchanger (NHE)3 phosphorylation at serine 552 and provoked a redistribution of NHE3, dipeptidyl peptidase IV (DPPIV), myosin VI, Na ϩ -Pi cotransporter (NaPi)-2, ANG II type 2 receptor (AT2R), aminopeptidase N (APN), Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC2), epithelial Na ϩ channel (ENaC) ␤-subunit, and Na ϩ -K ϩ -ATPase (NKA) ␣1-and ␤ 1-subunits from low-density plasma membrane-enriched fractions to higher-density intracellular membrane-enriched fractions. NHE3, myosin VI, and AT 2R retraction to the base of the microvilli (MV) during HS was evident by confocal microscopy. HS did not change abundance of NHE3, NKCC, or NKA ␣ 1-or ␤1-subunits but increased ENaC-␤ in high-density intracellular enriched membranes. Responses to HS were fully apparent after just 18 h. We propose that retraction of NHE3 to the base of the MV, driven by myosin VI and NHE3 phosphorylation and accompanied by redistribution of the NHE3 regulator DPPIV, contributes to a decrease in proximal tubule Na ϩ reabsorption during HS and that redistribution of transporters out of low-density plasma membrane-enriched fractions in the thick ascending limb of the loop of Henle and distal nephron may also contribute to the homeostatic natriuretic response to HS diet. sodium chloride; kidney; natriuresis; salt-sensitive hypertension A HIGH DIETARY SODIUM LOAD provokes a thirst that increases extracellular fluid volume (ECFV), maintaining plasma Na ϩ concentration in a normal range (40). The kidneys affect natriuretic and diuretic responses to match salt and water output to intake and restore ECFV. If volume is not corrected, it provokes a generalized vascular contraction to normalize tissue blood flow, resulting in hypertension. Establishing the molecular mechanisms by which the kidney regulates Na ϩ and ECFV homeostasis under normal conditions is an important goal because it will identify candidates that may contribute to salt-sensitive hypertension (6). Na ϩ transport along the nephron can be regulated by altering 1) total transporter abundanc...

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