Genetic manipulation and genetic variation of the kallikrein-kinin system: impact on cardiovascular and renal diseases.

Abstract

Genetic manipulation of the kallikrein-kinin system (KKS) in mice, with either gain or loss of function, and study of human genetic variability in KKS components which has been well documented at the phenotypic and genomic level, have allowed recognizing the physiological role of KKS in health and in disease. This role has been especially documented in the cardiovascular system and the kidney. Kinins are produced at slow rate in most organs in resting condition and/or inactivated quickly. Yet the KKS is involved in arterial function and in renal tubular function. In several pathological situations, kinin production increases, kinin receptor synthesis is upregulated, and kinins play an important role, whether beneficial or detrimental, in disease outcome. In the setting of ischemic, diabetic or hemodynamic aggression, kinin release by tissue kallikrein protects against organ damage, through B2 and/or B1 bradykinin receptor activation, depending on organ and disease. This has been well documented for the ischemic or diabetic heart, kidney and skeletal muscle, where KKS activity reduces oxidative stress, limits necrosis or fibrosis and promotes angiogenesis. On the other hand, in some pathological situations where plasma prekallikrein is inappropriately activated, excess kinin release in local or systemic circulation is detrimental, through oedema or hypotension. Putative therapeutic application of these clinical and experimental findings through current pharmacological development is discussed in the chapter.

• Authors: Jean-Pierre Girolami, Nelly Blaes, Nadine Bouby, François Alhenc-Gelas
• Journal: Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques (Prog Drug Res) Vol. 69 Pg. 145-96 ( 2014) ISSN: 0071-786X [Print] Switzerland
• PMID: 25130042 (Publication Type: Journal Article, Review)

Chemical References

• Cardiovascular Agents
• Kinins
• Renal Agents
• Kallikreins

Topics

• Animals
• Cardiovascular Agents (therapeutic use)
• Cardiovascular Diseases (drug therapy, enzymology, genetics, physiopathology)
• Genetic Predisposition to Disease
• Genetic Variation
• Humans
• Kallikreins (genetics, metabolism)
• Kidney Diseases (drug therapy, enzymology, genetics, physiopathology)
• Kinins (genetics, metabolism)
• Phenotype
• Renal Agents (therapeutic use)
• Signal Transduction