Antihypertensive role of tissue kallikrein in hyperaldosteronism in the mouse.
Tissue kallikrein (TK) is synthesized in arteries and distal renal tubule, the main target of aldosterone. Urinary kallikrein excretion increases in hyperaldosteronism. We tested the hypothesis that TK is involved in the cardiovascular and renal effects of high aldosterone. Kallikrein-deficient mice (TK-/-), and wild-type (WT) littermates, studied on two different genetic backgrounds, were treated with aldosterone and high-NaCl diet for 1 month. Control mice received vehicle and standard NaCl diet. Treatment induced 5- to 7-fold increase in plasma aldosterone, suppressed renin secretion, and increased urinary TK activity. In 129SvJ-C57BL/6J mice, blood pressure monitored by radiotelemetry was not different between control TK-/- and WT mice. In TK-/- mice, aldosterone induced larger increases in blood pressure than in WT mice (+47 vs. +27 mm Hg; genotype-treatment interaction, P < 0.05). Night-day difference was also exacerbated in treated TK-/- mice (P < 0.01). Moderate cardiac septal hypertrophy was observed in hypertensive animals without major change in heart function. Aldosterone-salt increased kidney weight similarly in both genotypes but induced a 2-fold increase in renal mRNA abundance of epithelial sodium channel subunits only in TK-/- mice. The hypertensive effect of TK deficiency was also documented in treated C57BL/6J mice. In this strain, aldosterone-induced hypertension was only observed in TK-/- mice (+16 mm Hg, P < 0.01). These findings show that TK deficiency exacerbates aldosterone-salt-induced hypertension. This effect may be due at least in part to enhanced sodium reabsorption in the distal nephron aggravating sodium retention. The study suggests that kallikrein plays an antihypertensive role in hyperaldosteronism.
Institut National de la Santé et de la Recherche Médicale Unité 872, Centre de Recherches des Cordeliers, 15 Rue de l'Ecole de Médecine, 75006 Paris, France.
Ludovic
L
Waeckel
Louis
L
Potier
Catherine
C
Chollet
Christopher
C
Taveau
Patrick
P
Bruneval
Ronan
R
Roussel
François
F
Alhenc-Gelas
Nadine
N
Bouby
D000450:Aldosterone / Q000097:blood / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D006929:Hyperaldosteronism / Q000178:diet therapy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012965:Sodium Chloride / Q000627:therapeutic use; D017673:Sodium Chloride, Dietary / Q000627:therapeutic use; D020840:Tissue Kallikreins / Q000235:genetics / Q000378:metabolism*
D000959:Antihypertensive Agents; D017673:Sodium Chloride, Dietary; D012965:Sodium Chloride; D000450:Aldosterone; D020840:Tissue Kallikreins; D012083:Renin