The kallikrein-kinin system in health and in diseases of the kidney

Abstract

Since kallikrein was discovered as a vasodilatory substance in human urine, the kallikrein-kinin system (KKS) has been considered to play a physiological role in controlling blood pressure. Gene targeting experiments in mice in which the KKS has been inactivated to varying degrees have, however, questioned this role, because basal blood pressures are not altered. Rather, these experiments have shown that the KKS has a different and important role in preventing changes associated with normal senescence in mice, and in reducing the nephropathy and accelerated senescence-associated phenotypes induced in mice by diabetes. Other experiments have shown that the KKS suppresses mitochondrial respiration, partly by nitric oxide and prostaglandins, and that this suppression may be a key to understanding how the KKS influences senescence-related diseases. Here we review the logical progression and experimental data leading to these conclusions, and discuss their relevance to human conditions.

Figure 1. Components and signaling of the KKS

(a) Biosynthesis and metabolism of kinins. CPM, carboxypeptidase-M; ACE, angiotensin I-converting enzyme; NEP, neprilysin (endopeptidase 24.11); ECE, endothelin-converting enzyme; red, active peptides; blue, inactive peptides. (b) Binding of kinins to bradykinin receptors and two intracellular mechanisms for suppression of oxidative metabolism. The thickness of arrows arising from the kinins indicates the relative potency of each peptide to elevate intracellular calcium concentrations. PIP₂, phosphatidylinositol-4,5-bisphosphate; PI-PLC, phosphatidylinositol-specific phospholipase C; IP₃, 1,4,5-inositol triphosphate; ER, endoplasmic reticulum; PL, phospholipids; PLA2, phospholipase A2.

Figure 2. Senescence-associated indices in the kidney of B2R-null and/or Akita diabetic mice

(a) Periodic acid-Schiff-stained kidneys of 12-month-old male mice (bar = 10 µm). Note the intracellular pigmented vacuoles in the cytoplasm of the proximal tubular epithelial cells of the Akita diabetic mice (Ins2 ^Akita/+), and their greater prominence when the diabetic mice also lack B2R (bdkrb2^−/−). (b) Transmission electron micrograph of a renal proximal tubule cell from a 12-month-old doubly mutant mouse (bar= 1 µm). There are numerous phagolysosomes containing lipid debris with focal lamination (arrows). (c) Frequencies of point mutations in mitochondrial DNA. (d) Relative proportion of D-17 deletions in mitochondrial DNA.