Martínez Jm

Renal aminopeptidase activities in animal models of hypertension

Aminopeptidase activity (AP) has been implicated in the metabolism of renal and circulating vasoactive peptides. This activity is involved in the pathogenia of hypertension, essentially in spontaneously hypertensive rats. However, no other animal models, which develop hypertension by other different ways, have been used to study the possible role of aminopeptidase activity. To investigate the role of this activity in the pathogenesis of hypertension, angiotensinase A activity (glutamyl-AP and aspartyl-AP), aminopeptidase M activity (alanyl-AP), aminopeptidase B activity (arginyl-AP), pyroglutamyl-AP, and cystinyl-AP were measured in the serum and kidney of two experimental animal models of renovascular hypertension: Goldblatt two-kidney one clip (G2K-1C) and low renal mass rats (LRM). No differences were found in serum levels of AP in LRM or G2K-1C in comparison with their respective controls. In LRM rats there was a significant decrease in membrane-bound angiotensinase A (glutamyl-AP), arginyl-AP and alanyl-AP activities. In G2K-1C rats there was a significant decrease in soluble and membrane-bound angiotensinase A activity (aspartyl-AP). Our results suggest that AP activities play a role in the regulation of renal vasoactive peptides, and respond differently depending on the cause of hypertension.

Aminopeptidase activities after water deprivation in male and female rats

Aminopeptidases (APs) play a major role in the metabolism of circulating and local peptides, such as angiotensins and vasopressin, substances involved in the control of blood pressure and water balance. In the present work, we studied the influence of dehydration on angiotensinases and vasopressin-degrading activity. Since sex differences may exist in the regulation of water balance by angiotensin II and differential sexual steroid modulation of vasopressin secretion, in response to osmotic stimulation have been reported, gonadotropin releasing hormone (GnRH)-degrading activity was also analysed in serum, neurohypophysis and adrenal glands of male and female rats. Our results did not suggest sex differences in the response to changes in osmolality. GnRH-degrading activity decreased in serum of dehydrated males and females, which suggests a longer action of the peptide under these conditions. In neurohypophysis, there was an increase in the activity of aminopeptidase A (APA), the enzyme responsible for the metabolism of angiotensin II to angiotensin III. This occurs with a decrease in alanyl aminopeptidase activity, which would lead to a prolonged action of angiotensin III by reduction of its metabolism. In adrenals of dehydrated animals, the results would imply a high degree of metabolism of angiotensin III and vasopressin.

Dietary supplementation with olive oil influences aminopeptidase activities in mice

Abstract We compared the effect of a low fat diet and an high fat diet containing olive oil (20% wt/wt) on soluble and membrane-bound aminopeptidase activities, in serum and selected tissues of male mice. After ten weeks of feeding, serum total cholesterol was determined colourimetrically. Alanyl-, arginyl- and cystinyl-aminopeptidase activities were measured fluorometrically using arylamide derivatives as substrates. Mice fed with the olive oil-supplemented diet had higher rates of weight gain than controls from the second week of feeding. Serum total cholesterol concentrations were higher after feeding the olive oil diet than after feeding the control diet. In serum, the olive oil-fed group had significantly higher arginyl-aminopeptidase activity levels than controls. Soluble alanyl- and arginyl-aminopeptidase activities increased significantly in the brain, adrenal gland and testis of olive oil-fed animals. Soluble cystinyl-aminopeptidase activity increased significantly in testes and liver and decreased in the adrenal glands of olive oil-fed mice. There was a significant decrease in membranebound cystinyl-aminopeptidase activity in the adrenal glands of olive oil-fed mice. These findings show that a diet supplemented with olive oil modifies certain aminopeptidase activities in specific tissues. The results may reflect functional modifications in susceptible endogenous substrates.

Lateralization of aminopeptidase A activity in substantia nigra, striatum and frontal cortex of rats ☆

Several brain aminopeptidase activities have been reported to be asymmetrical, but no direct correlation with lateralized functions has been proposed. Cholecystokinin (CCK) coexists with dopamine (DA) in the nigrostriatal system, which is involved in lateralized motor behaviors. Because aminopeptidase A activity is probably responsible for the hydrolysis of CCK, we studied the left-right distribution of glutamate- (GluAP) and aspartate-aminopeptidase (AspAP) activities in their soluble (Sol) and membrane-bound (M-B) forms in the substantia nigra, striatum and cortex of rats. Although there was a highly significant predominance of the left side in the substantia nigra and striatum for Sol GluAP and M-B AspAP respectively, in the frontal cortex predominance was on the right side for M-B AspAP. These results suggest a relationship between aminopeptidase A activity and lateralized nigro-striato-cortical functions involving CCK.

Pyroglutamyl peptidase I levels and their left-right distribution in the rat retina and hypothalamus are influenced by light-dark conditions

To evaluate the effects of light and darkness on pyroglutamyl peptidase I activity (pGluPI) and its left-right distribution, pGluPI was measured bilaterally in the retina and hypothalamus under selected light-dark schedules. Rats under a 12 h light-dark cycle were divided into four experimental groups. After the end of the 12 h dark period, the animals were kept two additional hours in darkness (group 1), or light (group 2). After the end of the 12 h light period, the animals were kept two additional hours in darkness (group 3), or light (group 4). Experiments were done in light or darkness depending on the 2 h period. In the retina, a previous 12 h light period led to higher values of enzyme activity than dark periods. Left-right predominance, however, depended on the previous 2 h period: the light period led to left predominance, whereas right predominance was found after the 2 h dark period. In the hypothalamus, a left predominance was found only in group 3. These results demonstrate that environmental light conditions influence pGluPI activity in the rat retina and hypothalamus.

Environmental Light-Darkness Conditions Induce Changes in Brain and Peripheral Pyroglutamyl-Peptidase I Activity

To evaluate the influence of light and darkness on brain pyroglutamyl-peptidase I (pGluPI) activity, four experimental groups of rats were compared at the same time-point (10.00 h). Two groups were designed with a standard 12-12 h light-dark cycle: In group A, the lights were on from 7.00 h to 19.00 h, and the experiment was done under light conditions; in group B, the lights were on from 19.00 h to 7.00 h, and the experiment was done under darkness conditions. Two additional groups were designed with nonstandard light-dark conditions: In group C, the animals were subjected to constant light, and the experiment was done under light conditions. In group D, animals were subjected to constant darkness, and the experiment was done under darkness conditions. Light (vs darkness) and standard (vs nonstandard) conditions produced significant changes on pGluPI activity in specific structures; the data suggested that endogenous substrates of pGluPI such as thyrotropin-releasing hormone and gonadotropin-releasing hormone, might be modified in parallel. There was left predominance in the retina under light conditions on a standard schedule (group A). The regional pattern of distribution of activity was similar in groups on a standard schedule (A vs B) and in groups tested under constant light-dark conditions (C vs D). However, this pattern differed between groups subjected to standard vs constant light-dark conditions (A and B vs C and D). These results support an influence of environmental light and darkness on pGluPI activity, which may reflect concomitant changes in its susceptible substrates and consequently in their functions.

Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target

Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.

Do the Effects of Resveratrol on Thermogenic and Oxidative Capacities in IBAT and Skeletal Muscle Depend on Feeding Conditions

The aim of this study was to compare the effects of mild energy restriction and resveratrol on thermogenic and oxidative capacity in interscapular brown adipose tissue (IBAT) and in skeletal muscle. Rats were fed a high-fat high-sucrose diet for six weeks, and divided into four experimental groups fed a standard diet: a control group, a resveratrol-treated group, an energy-restricted group and an energy-restricted group treated with resveratrol. Weights of IBAT, gastrocnemius muscle and fat depots were measured. Activities of carnitine palmitoyltransferase (CPT) and citrate synthase (CS), protein levels of sirtuin (SIRT1 and 3), uncoupling proteins (UCP1 and 3), glucose transporter (GLUT4), mitochondrial transcription factor (TFAM), nuclear respiratory factor (NRF1), peroxisome proliferator-activated receptor (PPARα) and AMP activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator (PGC1α) activation were measured. No changes in IBAT and gastrocnemius weights were found. Energy-restriction, but not resveratrol, decreased the weights of adipose depots. In IBAT, resveratrol enhanced thermogenesis activating the SIRT1/PGC1α/PPARα axis. Resveratrol also induced fatty acid oxidation and glucose uptake. These effects were similar when resveratrol was combined with energy restriction. In the case of gastrocnemius muscle, the effects were not as clear as in the case of IBAT. In this tissue, resveratrol increased oxidative capacity. The combination of resveratrol and energy restriction seemingly did not improve the effects induced by the polyphenol alone.

Interaction between an ADCY3 Genetic Variant and Two Weight-Lowering Diets Affecting Body Fatness and Body Composition Outcomes Depending on Macronutrient Distribution: A Randomized Trial

The adenylate cyclase 3 (ADCY3) gene is involved in the regulation of several metabolic processes including the development and function of adipose tissue. The effects of the ADCY3 rs10182181 genetic variant on changes in body composition depending on the macronutrient distribution intake after 16 weeks of the dietary intervention were tested. The ADCY3 genetic variant was genotyped in 147 overweight or obese subjects, who were randomly assigned to one of the two diets varying in macronutrient content: a moderately-high-protein diet and a low-fat diet. Anthropometric and body composition measurements (DEXA scan) were recorded. Significant interactions between the ADCY3 genotype and dietary intervention on changes in weight, waist circumference, and body composition were found after adjustment for covariates. Thus, in the moderately-high-protein diet group, the G allele was associated with a lower decrease of fat mass, trunk and android fat, and a greater decrease in lean mass. Conversely, in the low-fat diet group carrying the G allele was associated with a greater decrease in trunk, android, gynoid, and visceral fat. Subjects carrying the G allele of the rs10182181 polymorphism may benefit more in terms of weight loss and improvement of body composition measurements when undertaking a hypocaloric low-fat diet as compared to a moderately-high-protein diet.