Abstract
We compared the regulation of the NaCl cotransporter (NCC) in adaptation to a low-K (LK) diet in male and female mice. We measured hydrochlorothiazide (HCTZ)-induced changes in urine volume (UV), glomerular filtration rate (GFR), absolute (ENa, EK), and fractional (FENa, FEK) excretion in male and female mice on control-K (CK, 1% KCl) and LK (0.1% KCl) diets for 7 days. With CK, NCC-dependent ENa and FENa were larger in females than males as observed previously. However, with LK, HCTZ-induced ENa and FENa increased in males but not in females, abolishing the sex differences in NCC function as observed in CK group. 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. We also examined LK-induced changes in Na transport protein expression by Western blotting. Under CK conditions females expressed more NCC protein, as previously reported. LK doubled both total (tNCC) and phosphorylated NCC (pNCC) abundance in males but had more modest effects in females. The larger effect in males abolished the sex-dependence of NCC expression, consistent with the measurements of function by renal clearance. LK intake did not change NHE3, NHE2, or NKCC2 expression, but reduced the amount of the cleaved (presumably active) form of γENaC. LK reduced plasma K to lower levels in females than males. These results indicated that males had a stronger NCC-mediated adaptation to LK intake than females.
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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