Summary
Study of mice rendered deficient in tissue kallikrein (TK) by gene inactivation and
human subjects partially deficient in TK activity as consequence of an active site
mutation has allowed recognising the physiological role of TK and its peptide products
kinins in arterial function and in vasodilatation, in both species. TK appears as
the major kinin forming enzyme in arteries, heart and kidney. Non-kinin mediated actions
of TK may occur in epithelial cells in the renal tubule. In basal condition, TK deficiency
induces mild defective phenotypes in the cardiovascular system and the kidney. However,
in pathological situations where TK synthesis is typically increased and kinins are
produced, TK deficiency has major, deleterious consequences. This has been well documented
experimentally for cardiac ischaemia, diabetes renal disease, peripheral ischaemia
and aldosterone-salt induced hypertension. These conditions are all aggravated by
TK deficiency. The beneficial effect of ACE/kininase II inhibitors or angiotensin
II AT1 receptor antagonists in cardiac ischaemia is abolished in TK-deficient mice,
suggesting a prominent role for TK and kinins in the cardioprotective action of these
drugs. Based on findings made in TK-deficient mice and additional evidence obtained
by pharmacological or genetic inactivation of kinin receptors, development of novel
therapeutic approaches relying on kinin receptor agonism may be warranted.
Keywords
Kallikrein - kinins - ischaemia - diabetes mellitus - hypertension