Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

Abstract

Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to ␤-adrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.

Tissue kallikrein permits early renal adaptation to potassium load

“…Thus, the absence of TK decreases ENaC proteolysis and activation (34), but it up-regulates ENaC-independent electroneutral NaCl absorption presumably through a decrease in the local production of bradykinin. The combination of these two opposite effects can explain why TK −/− mice do not have a significantly altered sodium balance (34,36), but it might have important implications for renal potassium handling. Because K + secretion strictly depends on electrogenic Na + transport by ENaC, by favoring ENaC-mediated Na + absorption over electroneutral NaCl absorption, TK is expected to indirectly stimulate K + secretion by PCs (Fig.…”

“…Aldosterone synthase-deficient mice (AS −/− ) (38) were obtained from O. Smithies (University of North Carolina, Chapel Hill). Mice heterozygous for TK or AS gene disruption were crossed, and wild-type (TK +/+ or AS +/+ ) and homozygous knock-out mice (TK −/− or AS −/− ) were identified in their offspring by genotyping tail DNA as described in ref (36,38). In all experiments, controls consisted in wild-type littermates.…”

“…TK −/− mice have been generated in our laboratory (34,36,37). Aldosterone synthase-deficient mice (AS −/− ) (38) were obtained from O. Smithies (University of North Carolina, Chapel Hill).…”

The Kallikrein-Kinin System as a Regulator of Cardiovascular and Renal Function

“…Thus the components of the KKS are present in vascular tissue, where they could play an important role in regulation of vascular resistance. Arteries isolated from mice lacking the kallikrein gene reportedly exhibited significantly reduced flow-induced dilatation compared to controls, suggesting that the KKS in the arterial wall participates in this process (25,168). Moreover, in humans a partial genetic deficiency of TK (R53H) was associated with inward remodeling of the brachial artery that renders it incapable of adapting to a chronic increase in wall shear stress, a form of arterial dysfunction that affects 5% to 7% of Caucasians (13).…”

“…However, mice lacking TK have normal blood pressure and yet both the structure and function of the heart are clearly abnormal (168). Chronic blockade of B 2 receptors with a potent and selective antagonist, icatibant, did not increase blood pressure under normal conditions or in situations that favor hypertension in rats, such as (i) chronic infusion of a subpressor or pressor dose of angiotensin II (Ang II), (ii) a high salt diet, or (iii) mineralocorticoids and salt (148,229).…”