Tissue Kallikrein In Hypertension

a dominant gene expressed as renal or urinary kallikrein may be associated with a reduced risk of hypertension (16). This finding suggests that high urinary kallikrein may have a protective effect against the development of high blood pressure.

Reduced urinary kallikrein excretion has also been described in a number of genetically hypertensive rat models such as spontaneously hypertensive rats (SHR), New Zealand rats, Fawn-Hooded rats, and Dahl salt-sensitive (DSS) hypertensive rats (1721). Kinin appears to play a role in blood pressure regulation in SHR fed a salt-deficient diet, because the administration of a BK antagonist caused an increase in blood pressure (22). Furthermore, kininogen-deficient (Brown Norway-Katholiek) rats, which cannot generate kinin, are susceptible to the development of salt-induced hypertension (23). Several restriction fragment length polymorphisms have been mapped in the rat tissue kallikrein gene, and their regulatory regions have been identified in the SHR model (24). These findings indicate a possible difference in the tissue kallikrein gene locus between SHR and normotensive Wistar-Kyoto rats. Moreover, a tissue kallikrein RFLP has been shown to cosegregate with high blood pressure in the F2 offspring of SHR and normotensive Brown Norway-Katholiek crosses (25), suggesting a close linkage between the kallikrein gene locus and the hypertensive phenotype in SHR.

We have shown that transgenic mice and rats overexpressing human tissue kallikrein were permanently hypotensive throughout their lifetime compared with their control littermates (26-29). Administration of aprotinin or icatibant to the transgenic mice raised their blood pressures to normal levels (26,27). These results indicate that the expression of functional human tissue kallikrein can permanently alter the blood pressure setting in the transgenic animals, and that the effect is mediated by the BK B2 receptor. This conclusion is further reinforced by a study showing that transgenic mice overexpressing human BK B2 receptor are hypotensive when compared with their control littermates (30). Moreover, ablation of the B2 receptor gene in mice causes salt-sensitive hypertension (31). Taken together, these findings provide the first direct evidence demonstrating the role of the KKS in blood pressure regulation in vivo and lend support to the hypothesis that elevated levels of tissue kallikrein may offer a protective effect in preventing the development of hypertension and cardiovascular and renal complications.

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