Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans.
Tissue kallikrein (TK), the major kinin-forming enzyme, is synthesized in several organs, including the kidney and arteries. A loss-of-function polymorphism of the human TK gene (R53H) induces a substantial decrease in enzyme activity. As inactivation of the TK gene in the mouse induces endothelial dysfunction, we investigated the vascular, hormonal, and renal phenotypes of carriers of the 53H allele. In a crossover study, 30 R53R-homozygous and 10 R53H-heterozygous young normotensive white males were randomly assigned to receive both a low sodium-high potassium diet to stimulate TK synthesis and a high sodium-low potassium diet to suppress TK synthesis, each for 1 week. Urinary kallikrein activity was 50-60% lower in R53H subjects than in R53R subjects. Acute flow-dependent vasodilatation and endothelium-independent vasodilatation of the brachial artery were both unaffected in R53H subjects. In contrast, R53H subjects consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared with R53R subjects. Renal and hormonal adaptation to diets was unaffected in R53H subjects. The partial genetic deficiency in TK activity is associated with an inward remodeling of the brachial artery, which is not adapted to a chronic increase in wall shear stress, indicating a new form of arterial dysfunction affecting 5-7% of white people.
Azizi
Michel
M
Centre d'Investigations Cliniques 9201, Assistance Publique des Hôpitaux de Paris and INSERM, Université Paris V, Paris, France. michel.azizi@egp.ap-hop-paris.fr
Boutouyrie
Pierre
P
Bissery
Alvine
A
Agharazii
Mohsen
M
Verbeke
Francis
F
Stern
Nora
N
Bura-Rivière
Alessandra
A
Laurent
Stéphane
S
Alhenc-Gelas
François
F
Jeunemaitre
Xavier
X
D000328:Adult; D000450:Aldosterone / Q000097:blood / Q000652:urine; D000818:Animals; D001158:Arteries / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000097:blood; D001916:Brachial Artery / Q000033:anatomy & histology / Q000502:physiology; D018592:Cross-Over Studies; D004032:Diet; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D010641:Phenotype; D011110:Polymorphism, Genetic; D011188:Potassium / Q000378:metabolism; D011498:Protein Precursors / Q000097:blood; D011897:Random Allocation; D012083:Renin / Q000097:blood; D012964:Sodium / Q000378:metabolism; D013314:Stress, Mechanical; D020840:Tissue Kallikreins / Q000235:genetics* / Q000652:urine*; D014664:Vasodilation / Q000502:physiology
D011498:Protein Precursors; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D012964:Sodium; D020840:Tissue Kallikreins; D012083:Renin; D011188:Potassium