Partial human genetic deficiency in tissue kallikrein activity and renal calcium handling.
A loss-of-function polymorphism of the human tissue kallikrein (TK) gene (R53H) induces a major decrease in enzyme activity. Inactivation of the TK gene in mice causes a defect in tubular calcium (Ca) reabsorption. Therefore, this study investigated the Ca phenotype of carriers of the 53H allele. In a crossover study, 30 R53R homozygous and 10 R53H heterozygous young white male individuals were randomly assigned to two 7-d low-Ca diets (10 mmol/d) associated with either a low-sodium (Na)/high-potassium (K) diet or a high-Na/low-K diet to modulate TK synthesis. On the seventh day of each diet, the participants were studied before and during a 2-h infusion of furosemide that functionally excludes the thick ascending limb and increases Ca delivery to distal tubular segments. Urinary kallikrein activity was 50 to 60% lower in R53H participants than in R53R participants. Adaptation of urinary Ca excretion to the contrasted Na/K diets was unaffected in R53H participants. By contrast, R53H participants after furosemide infusion had significantly lower serum ionized Ca concentrations than did R53R participants (P < 0.0001) and tendency toward nonsignificantly higher urinary Ca excretions than did R53R participants (P = 0.14). These effects were more marked under low-Na/high-K diet. Despite nonsignificant differences in urinary Ca excretions between the two groups, these results suggest in R53H individuals an increase in Ca reabsorption in the thick ascending limb under baseline conditions that counteracts a distal tubular defect that is revealed by furosemide infusion. In humans as in mice, TK thus may act as an intrarenal modulator of Ca reabsorption.
Blanchard
Anne
A
Centre d'Investigation Cliniques, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, F-75015 Paris, France. anne.blanchard@egp.aphp.fr
Azizi
Michel
M
Peyrard
Séverine
S
Stern
Nora
N
Alhenc-Gelas
François
F
Houillier
Pascal
P
Jeunemaitre
Xavier
X
D000293:Adolescent; D000328:Adult; D002118:Calcium / Q000378:metabolism*; D018592:Cross-Over Studies; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D020840:Tissue Kallikreins / Q000235:genetics* / Q000502:physiology*
D020840:Tissue Kallikreins; D002118:Calcium