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Thromb Haemost 2013; 110(03): 476-483
DOI: 10.1160/TH12-12-0937
Theme Issue Article
Schattauer GmbH

Pathophysiology of genetic deficiency in tissue kallikrein activity in mouse and man

Ludovic Waecke
1   INSERM U872, Centre de Recherche des Cordeliers, Paris-Descartes Université, Pierre et Marie Curie Université, Paris, France
,
Louis Potier
1   INSERM U872, Centre de Recherche des Cordeliers, Paris-Descartes Université, Pierre et Marie Curie Université, Paris, France
,
Christine Richer
1   INSERM U872, Centre de Recherche des Cordeliers, Paris-Descartes Université, Pierre et Marie Curie Université, Paris, France
,
Ronan Roussel
1   INSERM U872, Centre de Recherche des Cordeliers, Paris-Descartes Université, Pierre et Marie Curie Université, Paris, France
,
Nadine Bouby
1   INSERM U872, Centre de Recherche des Cordeliers, Paris-Descartes Université, Pierre et Marie Curie Université, Paris, France
,
Francois Alhenc-Gelas
1   INSERM U872, Centre de Recherche des Cordeliers, Paris-Descartes Université, Pierre et Marie Curie Université, Paris, France
› Author Affiliations Financial Support: This work was supported by Institut National de la Sante et de la Recherche medicale, Paris-Descartes University, the European Vascular Genomics Network, a Network of Excellence supported by the European Community’s sixth Framework Program for Research Priority 1“Life sciences, genomics and biotechnology for health” (LSHMCT-2003-503254), the National Research Agency (ANR 05-PCOD-027), and the French Society of Nephrology and the French Diabetes Society.
Further Information

Publication History

Received: 20 December 2012

Accepted after major revision: 14 March 2013

Publication Date:
22 November 2017 (online)

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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
 

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