The kallikrein-kinin system and oxidative stress

Abstract

Purpose of review: The kallikrein-kinin system (KKS) constitutes a complex multienzyme cascade that produces several bioactive kinin peptides and their derivatives including bradykinin. In addition to the classical notion of the KKS as a potent vasodilator and a mediator of inflammatory responses, recent studies suggest a link between the KKS and oxidative stress. A number of established mouse models with altered levels of KKS components opened the way to evaluate precise functions of the KKS. Here we review recent findings on the role of the KKS in cardiovascular diseases and chronic kidney diseases, and discuss potential benefits of KKS activation in these diseases.

Recent findings: Deletion of both B1R and B2R in a diabetic mouse model exacerbates its renal phenotypes, suggesting that the KKS exerts protective effects on diabetic nephropathy by suppressing oxidative stress, presumably via nitric oxide and prostaglandins.

Summary: Accumulating evidence has highlighted the importance of the KKS as a protective system against oxidative stress and organ damage in the heart and kidney. The activation of the KKS by angiotensin I-converting enzyme inhibitors and vasopeptidase inhibitors is likely to be beneficial in senescence-associated cardiovascular diseases and chronic kidney diseases.

Figure 1. The KKS and suppression of oxidative stress

Kinins are generated from kininogens by kallikreins and are inactivated by ACE, NEP and ECE. Binding of kinins to bradykinin receptors (B1R and B2R) leads to the reduction of oxidative stress via NO and PGs. NEP, neprilysin; ECE, endothelin-converting enzyme.

Figure 2. Pathological changes in the B1RB2R-null/Akita mice

PAS staining of renal glomeruli in 12-month-old male WT, B2R-null, B1RB2R-null, Akita, B2R-null, and B1RB2R-null/Akita mice. Lack of bradykinin receptors enhances diabetic glomerulosclerosis. Scale bar, 100 μm. Reproduced with permission from: [31**].