Abstract
The thiazide sensitive Na‐Cl co‐transporter (NCC) in the distal tubule can be regulated by dietary potassium intake and is critical for electrolyte homeostasis. Previously we reported that there was higher NCC activity and expression in female over male mice and high‐K intake preserved the sex‐difference of NCC‐mediated sodium absorption due to comparable reductions of NCC activity and expression in both sexes. However, with high‐K intake hydrochlorothiazide (HCTZ)‐induced kaliuresis was greater in males than in female mice, suggesting a more powerful male adaptation to high‐K intake. In this study, we explored the role of NCC in adaptation to a low‐K (LK) diet. We measured HCTZ‐induced changes in urine volume (UV), glomerular filtration rate (GFR), absolute (ENa, EK) and fractional (FENa, FEK) cation excretion in male and female mice on control‐K (CK, 1% KCl) and LK (0.1%, KCl) diets for 7 days. We also examined LK‐induced changes in NCC, Na/H‐exchanger isoform 3 (NHE3), and ENaC protein expression by Western blotting. With CK, NCC‐dependent ENa and FENa were larger in females than males as we observed previously. However with LK HCTZ‐induced ENa and FENa increased in males but not in females. Thus K restriction abolished the sex differences in NCC function. Changes in total NCC protein followed a similar pattern. Under CK conditions females expressed more NCC protein, as previously reported. LK increased NCC abundance in both males (by 100%) and females (by 40%). The larger effect in males reversed the sex‐dependence of NCC expression, consistent with the measurements of function. LK intake did not change either NHE3 or NHE2 expression, but reduced the amount of cleaved (presumably active) forms of α and γENaC expression in males but not in females. Thus decreased Na reabsorption through ENaC may compensate for increased Na transport through NCC in males. Despite large diuretic and natriuretic responses to HCTZ, EK was only slightly increased in response to the drug when animals were on LK. This suggests that the K‐secretory apparatus in the distal nephron is strongly suppressed under these conditions.Support or Funding InformationNIH NIDDK RO1 DK099284
Highlights
The thiazide sensitive Na-Cl co-transporter (NCC) is the major transporter for sodium and chloride reabsorption in the distal convoluted tubule (DCT) (8, 15, 21, 31)
High K intake decreases NCC expression and activity, leading to reduction of Na and Cl absorption in the DCT and increasing N a+ and fluid delivery to the distal nephron leading to stimulation of K+ secretion (30, 33, 36, 37)
We investigated the sex differences in adaptation to LK intake
Summary
The thiazide sensitive Na-Cl co-transporter (NCC) is the major transporter for sodium and chloride reabsorption in the distal convoluted tubule (DCT) (8, 15, 21, 31). NCC activity is regulated by the level of the total protein expression, the amount of protein at the apical membrane, and by phosphorylation or dephosphorylation of NCC, modulating uptake of N a+ and Cl− in the DCT (24). Variation of NCC activity is important to maintain normal electrolyte homeostasis under conditions of low or high dietary K intake (9). High K intake decreases NCC expression and activity, leading to reduction of Na and Cl absorption in the DCT and increasing N a+ and fluid delivery to the distal nephron leading to stimulation of K+ secretion (30, 33, 36, 37). Dietary restriction up-regulates NCC expression, increasing NaCl absorption in the DCT and reducing K+ secretion in more distal segments (11, 39)
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