Sex difference in kidney electrolyte transport II: impact of K+ intake on thiazide-sensitive cation excretion in male and female mice.

We studied sex differences in response to high K+ (HK) intake on thiazide-sensitive cation (Na+ and K+) excretion in wild-type (WT) and ANG II receptor subtype 1a (AT1aR) knockout (KO) mice. Renal clearance experiments were performed to examine Na+-Cl- cotransporter (NCC) activity on mice fed with control and HK (5% KCl, 7 days) diets. Hydrochlorothiazide (HCTZ)-induced changes in urine volume, glomerular filtration rate, absolute Na+ and K+ excretion, and fractional excretion were compared. HK-induced changes in NCC, Na+/H+ exchanger isoform 3 (NHE3), and ENaC expression were examined by Western blot analysis. In WT animals under the control diet, HCTZ-induced cation excretion was greater in female animals, reflecting larger increases in Na+ excretion, since there was little sex difference in HCTZ-induced K+ excretion. Under the HK diet, the sex difference in HCTZ-induced cation excretion was reduced because of larger increments in K+ excretion in male animals. The fraction of K+ excretion was 57 ± 5% in male WT animals and 36 ± 4% in female WT animals (P < 0.05), but this difference was absent in AT1aR KO mice. NCC abundance was higher in female animals than in male animals but decreased by similar fractions on HK diet. NHE3 abundance decreased, whereas cleaved forms of γ-ENaC increased, with HK in all groups; these changes were similar in male and female animals and were not significantly affected by AT1aR ablation. These results indicate that, with the HK diet, male animals display greater distal Na+ delivery and greater activation of K+ secretion mechanisms, all suggesting a more powerful male adaptation to HK intake.