title: Partial genetic deficiency in tissue kallikrein impairs adaptation to high potassium intake in humans.
abstract: Inactivation of the tissue kallikrein gene in mice impairs renal handling of potassium due to enhanced H, K-ATPase activity, and induces hyperkalemia. We investigated whether the R53H loss-of-function polymorphism of the human tissue kallikrein gene affects renal potassium handling. In a crossover study, 30 R53R homozygous and 10 R53H heterozygous healthy males were randomly assigned to a low-sodium/high-potassium or a high-sodium/low-potassium diet to modulate tissue kallikrein synthesis. On the seventh day of each diet, participants were studied before and during a 2-h infusion of furosemide to stimulate distal potassium secretion. Urinary kallikrein activity was significantly lower in R53H than in R53R subjects on the low-sodium/high-potassium diet and was similarly reduced in both genotypes on high-sodium/low-potassium. Plasma potassium and renal potassium reabsorption were similar in both genotypes on an ad libitum sodium/potassium diet or after 7 days of a high-sodium/low-potassium diet. However, the median plasma potassium was significantly higher after 7 days of low-sodium/high-potassium diet in R53H than in R53R individuals. Urine potassium excretion and plasma aldosterone concentrations were similar. On the low-sodium/high-potassium diet, furosemide-induced decrease in plasma potassium was significantly larger in R53H than in R53R subjects. Thus, impaired tissue kallikrein stimulation by a low-sodium/high-potassium diet in R53H subjects with partial tissue kallikrein deficiency highlights an inappropriate renal adaptation to potassium load, consistent with experimental data in mice.
authors.affiliation: Faculty of Medicine, Porto University, Porto, Portugal.
authors.forename: Joana S
authors.initials: JS
authors.lastname: Monteiro
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Curis
authors.forename: Régine
authors.initials: R
authors.lastname: Chambrey
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Michel
authors.initials: M
authors.lastname: Azizi
mesh_terms: D000222:Adaptation, Physiological; D000328:Adult; D000450:Aldosterone / Q000097:blood; D018592:Cross-Over Studies; D004039:Diet, Sodium-Restricted; D005665:Furosemide / Q000008:administration & dosage; D064368:Healthy Volunteers; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010641:Phenotype; D017419:Potassium, Dietary / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage; D013997:Time Factors; D020840:Tissue Kallikreins / Q000172:deficiency / Q000235:genetics*
chemical_list: D017419:Potassium, Dietary; D017673:Sodium Chloride, Dietary; D049994:Sodium Potassium Chloride Symporter Inhibitors; D000450:Aldosterone; D005665:Furosemide; D020840:Tissue Kallikreins