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

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

Transforming growth factor-β1 and diabetic nephropathy

Transforming growth factor-β1 (TGF-β1) is established to be involved in the pathogenesis of diabetic nephropathy. The diabetic milieu enhances oxidative stress and induces the expression of TGF-β1. TGF-β1 promotes cell hypertrophy and extracellular matrix accumulation in the mesangium, which decreases glomerular filtration rate and leads to chronic renal failure. Recently, TGF-β1 has been demonstrated to regulate urinary albumin excretion by both increasing glomerular permeability and decreasing reabsorption in the proximal tubules. TGF-β1 also increases urinary excretion of water, electrolytes and glucose by suppressing tubular reabsorption in both normal and diabetic conditions. Although TGF-β1 exerts hypertrophic and fibrogenic effects in diabetic nephropathy, whether suppression of the function of TGF-β1 can be an option to prevent or treat the complication is still controversial. This is partly because adrenal production of mineralocorticoids could be augmented by the suppression of TGF-β1. However, differentiating the molecular mechanisms for glomerulosclerosis from those for the suppression of the effects of mineralocorticoids by TGF-β1 may assist in developing novel therapeutic strategies for diabetic nephropathy. In this review, we discuss recent findings on the role of TGF-β1 in diabetic nephropathy

Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase

Prolactin is a hormone secreted by the pituitary gland that controls changes in the breast to enable milk production after the baby is born. In some mothers with pregnancy-related high blood pressure (BP), the concentration of prolactin in the blood is higher than normal, but whether this causes the high BP or is a consequence of it is uncertain. To answer this question, we have generated experimental mice that produce prolactin in the liver when we feed them a substance, indole-3-carbinol (IC3), that is found in broccoli. When fed normal chow, the mice are well, but, when fed IC3, they develop high BP and heart problems. This suggests that pregnant women with abnormally high prolactin levels may need special attention

Altering the Expression in Mice of Genes by Modifying Their 3′ Regions

Polymorphic differences altering expression of genes without changing their products probably underlie human quantitative traits affecting risks of serious diseases, but methods for investigating such quantitative differences in animals are limited. Accordingly, we have developed a procedure for changing the expression in mice of chosen genes over a 100-fold range while retaining their chromosomal location and transcriptional controls. To develop the procedure, we first dissected the effects in embryonic stem (ES) cells of elements within and downstream of the 3' untranslated region (UTR) of a single copy transgene at the Hprt locus. As expected, protein expression varied with the steady-state level and half-life of the mRNA. The rank order of expression with various tested 3' regions is the same in ES cells, and in cardiomyocytes and trophoblastocytes derived from them. In mice having two functionally different native genes with modified 3'UTRs, the desired expression was obtained

High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

About one-third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below-normal Elmo1 expression in mice ameliorates the albuminuria and glomerular histological changes resulting from long-standing type 1 diabetes, whereas above-normal Elmo1 expression makes both worse. Increasing Elmo1 expression leads to aggravation of oxidative stress markers and enhances the expression of fibrogenic genes. Suppressing Elmo1 action in human patients could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

About one third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below normal transforming growth factor (TGF) β1 expression ameliorates the nephropathy and decreased glomerular filtration rate resulting from long-standing type 1 diabetes, while above normal TGFβ1 expression makes both worse. Reducing TGFβ1 expression in the glomerulus is more important in avoiding the decrease in glomerular filtration rate than altering expression in the tubule, while expression in the tubule is more important in controlling interstitial fibrosis and albuminuria. Suppressing TGFβ1 action in the kidney as a whole, or specifically in podocytes, could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes

The kallikrein–kinin system in diabetic nephropathy

Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Although the renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy, angiotensin I-converting enzyme (ACE) inhibitors have a beneficial effect on diabetic nephropathy independently of their effects on blood pressure and plasma angiotensin II levels. This suggests that the kallikrein-kinin system (KKS) is also involved in the disease. To study the role of the KKS in diabetic nephropathy, mice lacking either the bradykinin B1 receptor (B1R) or the bradykinin B2 receptor (B2R) have been commonly used. However, because absence of either receptor causes enhanced expression of the other, it is difficult to determine the precise functions of each receptor. This difficulty has recently been overcome by comparing mice lacking both receptors with mice lacking each receptor. Deletion of both B1R and B2R reduces nitric oxide (NO) production and aggravates renal diabetic phenotypes, relevant to either lack of B1R or B2R, demonstrating that both B1R and B2R exert protective effects on diabetic nephropathy presumably via NO. Here, we review previous epidemiological and experimental studies, and discuss novel insights regarding the therapeutic implications of the importance of the KKS in averting diabetic nephropathy

Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade

Congestive heart failure develops in human patients and experimental animals when the left ventricle becomes dilated. In the present study, mice were generated having graded genetic levels of endothelin-1 from 20% normal to 350% normal by modifying the 3′ untranslated region of the endothelin-1 gene. The 20% and 65% hypomorphs develop dilated cardiomyopathy, whereas the 350% hypermorph has a hypertrophic heart. Increases in superoxide levels and overexpression of matrix metalloproteinase 9 (MMP9) are involved in the development of the dilated cardiomyopathy in the 20% hypomorph. Our results show that endothelin-1 is critical for maintaining normal cardiac contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching