Effects of Bradykinin B2 Receptor Ablation from Tyrosine Hydroxylase Cells on Behavioral and Motor Aspects in Male and Female Mice.

The kallikrein-kinin system is a versatile regulatory network implicated in various biological processes encompassing inflammation, nociception, blood pressure control, and central nervous system functions. Its physiological impact is mediated through G-protein-coupled transmembrane receptors, specifically the B1 and B2 receptors. Dopamine, a key catecholamine neurotransmitter widely distributed in the CNS, plays a crucial role in diverse physiological functions including motricity, reward, anxiety, fear, feeding, sleep, and arousal. Notably, the potential physical interaction between bradykinin and dopaminergic receptors has been previously documented. In this study, we aimed to explore whether B2R modulation in catecholaminergic neurons influences the dopaminergic pathway, impacting behavioral, metabolic, and motor aspects in both male and female mice. B2R ablation in tyrosine hydroxylase cells reduced the body weight and lean mass without affecting body adiposity, substrate oxidation, locomotor activity, glucose tolerance, or insulin sensitivity in mice. Moreover, a B2R deficiency in TH cells did not alter anxiety levels, exercise performance, or motor coordination in female and male mice. The concentrations of monoamines and their metabolites in the substantia nigra and cortex region were not affected in knockout mice. In essence, B2R deletion in TH cells selectively influenced the body weight and composition, leaving the behavioral and motor aspects largely unaffected.

Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain.

Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.

Cortisol Dose-Dependently Impairs Migration and Tube-like Formation in a Trophoblast Cell Line and Modulates Inflammatory and Angiogenic Genes.

Several stimuli can change maternal hormone levels during pregnancy. These changes may affect trophoblastic cells and modulate the development of the embryo and the placental tissue itself. Changes in cortisol levels are associated with impaired trophoblast implantation and function, in addition to other pregnancy complications. This study aims to analyze the effects of low and high doses of cortisol on an extravillous trophoblast cell line, and the effects of various exposures to this hormone. SGHPL-4 cells were treated with cortisol at five doses (0-1000 nM) and two exposures (continuous: 24 h/day; and intermittent: 2 h/day). In intermittent treatment, cortisol acted mainly as an anti-inflammatory hormone, repressing gene expression of kinin B1 receptors, interleukin-6, and interleukin-1ß. Continuous treatment modulated inflammatory and angiogenic pathways, significantly repressing angiogenic factors and their receptors. Cortisol affected cell migration and tube-like structures formation. In conclusion, both continuous and intermittent exposure to cortisol repressed the expression of inflammatory genes, while only continuous exposure repressed the expression of angiogenic genes, suggesting that a sustained increase in the levels of this hormone is more harmful than a high short-term increase. Cortisol also impaired tube-like structures formation, and kinin receptors may be involved in this response.

Effects of 12†weeks of resistance training on rat gut microbiota composition.

In addition to its health benefits, exercise training has been noted as a modulator of the gut microbiota. However, the effects of resistance training (RT) on gut microbiota composition remain unknown. Wistar rats underwent 12 weeks of RT. Body mass, glucose tolerance, visceral body fat, triglyceride concentration and food consumption were evaluated. The gut microbiota was analyzed by 16S rRNA gene sequencing. Rats that underwent RT showed lower body mass (P=0.0005), lower fat content (P=0.02) and better glucose kinetics (P=0.047) when compared with the control. Improvements in the diversity and composition of the gut microbiota were identified in the RT group. The relative abundance of Pseudomonas, Serratia and Comamonas decreased significantly after 12 weeks of RT (P<0.001). These results suggest that RT has the potential to enhance the diversity of the gut microbiota and improve its biological functions.

Interleukin-6 and the Gut Microbiota Influence Melanoma Progression in Obese Mice.

There is a strong correlation between obesity and cancer. Here, we investigated the influence of IL-6 and gut microbiota of obese mice in melanoma development. We first evaluated B16F10 melanoma growth in preclinical models for obesity: mice deficient for leptin (ob/ob) or adiponectin (AdpKO) and in wild-type mice (WT, C57BL/6J) fed a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. The survival rates of ob/ob and HFD-fed mice were lower than those of their respective controls. AdpKO mice also died earlier than WT control mice. We then verified the involvement of IL-6 signaling in obese mice that were inoculated with melanoma cells. Both ob/ob and AdpKO mice had higher circulating IL-6 levels than wild-type mice. Melanoma tumor volumes in IL-6 KO mice fed an HFD were reduced compared to those of WT mice subjected to the same diet. Also evaluated the effect of microbiota in tumor development. Cohousing and fecal matter transfer experiments revealed that microbiota from ob/ob mice can stimulate tumor development in lean WT mice. Taken together, our data show that in some conditions IL-6 and the gut microbiota are key mediators that link obesity and melanoma.

Bradykinin B2 Receptor Signaling Increases Glucose Uptake and Oxidation: Evidence and Open Questions.

The Kinin B2 receptor (B2R) is classically involved in vasodilation and inflammatory responses. However, through the observation of hypoglycemic effects of Angiotensin-I-Converting Enzyme (ACE) inhibitors, this protein has been related to metabolic glucose modulation in physiological and pathophysiological contexts. Although several studies have evaluated this matter, the different methodologies and models employed, combined with the distinct target organs, results in a challenge to summarize and apply the knowledge in this field. Therefore, this review aims to compile human and animal data in order to provide a big picture about what is already known regarding B2R and glucose metabolism, as well to suggest pending investigation issues aiming at evaluating the role of B2R in relation to glucose metabolism in homeostatic situations and metabolic disturbances. The data indicate that B2R signaling is involved mainly in glucose uptake in skeletal muscle and adipose tissue, acting as a synergic player beside insulin. However, most data indicate that B2R induces increased glucose oxidation, instead of storage, via activation of a broad signaling cascade involving Nitric Oxide (NO) and cyclic-GMP dependent protein kinase (PKG). Additionally, we highlight that this modulation is impaired in metabolic disturbances such as diabetes and obesity, and we provide a hypothetic mechanism to explain this blockade in light of literature data provided for this review, as well as other authors.

Chronic Overexpression of Bradykinin in Kidney Causes Polyuria and Cardiac Hypertrophy.

Acute intra-renal infusion of bradykinin increases diuresis and natriuresis via inhibition of vasopressin activity. However, the consequences of chronically increased bradykinin in the kidneys have not yet been studied. A new transgenic animal model producing an excess of bradykinin by proximal tubular cells (KapBK rats) was generated and submitted to different salt containing diets to analyze changes in blood pressure and other cardiovascular parameters, urine excretion, and composition, as well as levels and expression of renin-angiotensin system components. Despite that KapBK rats excrete more urine and sodium, they have similar blood pressure as controls with the exception of a small increase in systolic blood pressure (SBP). However, they present decreased renal artery blood flow, increased intrarenal expression of angiotensinogen, and decreased mRNA expression of vasopressin V1A receptor (AVPR1A), suggesting a mechanism for the previously described reduction of renal vasopressin sensitivity by bradykinin. Additionally, reduced heart rate variability (HRV), increased cardiac output and frequency, and the development of cardiac hypertrophy are the main chronic effects observed in the cardiovascular system. In conclusion: (1) the transgenic KapBK rat is a useful model for studying chronic effects of bradykinin in kidney; (2) increased renal bradykinin causes changes in renin angiotensin system regulation; (3) decreased renal vasopressin sensitivity in KapBK rats is related to decreased V1A receptor expression; (4) although increased renal levels of bradykinin causes no changes in mean arterial pressure (MAP), it causes reduction in HRV, augmentation in cardiac frequency and output and consequently cardiac hypertrophy in rats after 6 months of age.

Bradykinin B2 receptor is essential to running-induced cell proliferation in the adult mouse hippocampus.

Physical exercise is a strong external effector that induces precursor cell proliferation in the adult mouse hippocampus. Research into mechanisms has focused on central changes within the hippocampus and we have established that serotonin is the signaling factor that transduces physical activity into adult neurogenesis. Less focus has been given on potential peripheral signals that may cause pro-mitotic running effects. Vasoactive kinin peptides are important for blood pressure regulation and inflammatory processes to maintain cardiovascular homeostasis. Acting via the two receptors termed B1 (B1R) and B2R, the peptides also function in the brain. In particular, studies attribute B2R a role in cell proliferation and differentiation into neurons in vitro. Here, we determined B1R and B2R mRNA expression levels in the adult mouse hippocampus and prefrontal cortex in vivo, and in response to running exercise. Using mice depleted in either or both receptors, B1-knockout (KO), B2KO and B1/2KO we observed changes in running performance overnight and in running distances. However, voluntary exercise led to the known pro-mitotic effect in the dentate gyrus of B1KO mice while it was attenuated in B2KO accompanied by an increase in microglia cells. Our data identify B2R as an important factor in running-induced precursor cell proliferation.

The angiotensin-I-converting enzyme insertion/deletion in polymorphic element codes for an AluYa5 RNA that downregulates gene expression.

Angiotensin-I-converting enzyme (ACE) is involved in the synthesis and degradation of important bioactive peptides. The ACE gene has a 287-bp insertion/deletion polymorphism that controls ACE expression through a mechanism that remains elusive. In this study, we found that the 287-bp polymorphic element of the ACE gene, a member of the AluYa5 sub-family of Alu elements, codes for an RNA molecule that controls the levels of ACE mRNA. Transient transfection of a plasmid containing a CMV promoter upstream of the ACE polymorphic element resulted in significant expression of an AluYa5 RNA and reduced ACE mRNA expression as well as ACE enzymatic activity in AD 293 cells. The AluYa5 element also independently reduced the expression of other genes, regardless of whether these genes harbored Alu elements within their genomic context. Interestingly, the CMV promoter was not required for the expression of the AluYa5 element in AD 293 cells. The 287-bp sequence was sufficient to produce AluYa5 RNA and led to a significant reduction in ACE gene expression. Moreover, the removal of an 11-bp fragment of the 3' end of the ACE polymorphic sequence, which is specific to this particular AluYa5 element, did not prevent this element from being expressed but did affect its ability to target ACE expression. Thus, the expression of the AluYa5 polymorphic element within the ACE gene could explain why patients carrying the ACE insertion polymorphism have reduced risk of developing several chronic diseases.

Different metabolic responses induced by long-term interdisciplinary therapy in obese adolescents related to ACE I/D polymorphism.

INTRODUCTION: The main purpose of the present study was to investigate whether I/D polymorphism of the ACE gene might affect metabolic changes related to the metabolic syndrome through a long-term interdisciplinary therapy in obese adolescents. METHODS: In total, 125 obese adolescents who entered the interdisciplinary obesity programme were assigned to the following two subgroups: metabolic syndrome or non-metabolic syndrome. They were evaluated at baseline and after 1 year. Genomic DNA was extracted from circulating leukocytes. RESULTS: Subjects with the II genotype in the non-metabolic syndrome group were only to increase their fat-free mass after therapy. Regarding lipid profile, subjects with ID and DD genotypes from both groups reduced their low-density lipoprotein cholesterol levels significantly. The metabolic parameters from the ID and DD genotypes of the non-metabolic syndrome group showed a significantly improved insulin response. CONCLUSION: In the present study, we showed that the ACE polymorphism was able to influence the fat-free mass in the I-carry allele in the non-metabolic syndrome group positively. In addition, the I-carry allele was able to improve the insulin resistance of the metabolic syndrome group significantly. These results suggest that the ACE I/D genotypes can influence, in different ways, the specific parameters of metabolism among obese adolescents submitted for long-term interdisciplinary therapy.

Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation.

The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1ß and TNF-α levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-α was activated in mice after CR. An antagonist of PPAR-α blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-α activation.

MATE-1 modulation by kinin B1 receptor enhances cisplatin efflux from renal cells.

Cisplatin is a drug widely used in chemotherapy that frequently causes severe renal dysfunction. Organic transporters have an important role to control the absorption and excretion of cisplatin in renal cells. Deletion and blockage of kinin B1 receptor has already been show to protect against cisplatin-induced acute kidney injury. To test whether it exerts its protective function by modulating the organic transporters in kidney, we studied kinin B1 receptor knockout mice and treatment with a receptor antagonist at basal state and in presence of cisplatin. Cisplatin administration caused downregulation of renal organic transporters; in B1 receptor knockout mice, this downregulation of organic transporters in kidney was absent; and treatment by a B1 receptor antagonist attenuated the downregulation of the transporter MATE-1. Moreover, kinin B1 receptor deletion and blockage at basal state resulted in higher renal expression of MATE-1. Moreover we observed that kinin B1 receptor deletion and blockage result in less accumulation of platinum in renal tissue. Thus, we propose that B1 receptor deletion and blockage protect the kidney from cisplatin-induced acute kidney injury by upregulating the expression of MATE-1, thereby increasing the efflux of cisplatin from renal cells.

High aminopeptidase A activity contributes to blood pressure control in ob/ob mice by AT2 receptor-dependent mechanism.

Obesity is assumed to be a major cause of human essential hypertension; however, the mechanisms responsible for weight-related increase in blood pressure (BP) are not fully understood. The prevalence of hypertension induced by obesity has grown over the years, and the role of the renin-angiotensin-aldosterone system (RAAS) in this process continues to be elucidated. In this scenario, the ob/ob mice are a genetic obesity model generally used for metabolic disorder studies. These mice are normotensive even though they present several metabolic conditions that predispose them to hypertension. Although the normotensive trait in these mice is associated with the poor activation of sympathetic nervous system by the lack of leptin, we demonstrated that ob/ob mice present massively increased aminopeptidase A (APA) activity in the circulation. APA enzyme metabolizes angiotensin (ANG) II into ANG III, a peptide associated with intrarenal angiotensin type 2 (AT2) receptor activation and induction of natriuresis. In these mice, we found increased ANG-III levels in the circulation, high AT2 receptor expression in the kidney, and enhanced natriuresis. AT2 receptor blocking and APA inhibition increased BP, suggesting the ANG III-AT2 receptor axis as a complementary BP control mechanism. Circulating APA activity was significantly reduced by weight loss independently of leptin, indicating the role of fat tissue in APA production. Therefore, in this study we provide new data supporting the role of APA in BP control in ob/ob mouse strain. These findings improve our comprehension about obesity-related hypertension and suggest new tools for its treatment.NEW & NOTEWORTHY In this study, we reported an increased angiotensin III generation in the circulation of ob/ob mice caused by a high aminopeptidase A activity. These findings are associated with an increased natriuresis found in these mice and support the role of renin-angiotensin-aldosterone system as additional mechanism regulating blood pressure in this genetic obese strain.

Maternal Forced Swimming Reduces Cell Proliferation in the Postnatal Dentate Gyrus of Mouse Offspring.

Physical exercise positively affects the metabolism and induces proliferation of precursor cells in the adult brain. Maternal exercise likewise provokes adaptations early in the offspring. Using a high-intensity swimming protocol that comprises forced swim training before and during pregnancy, we determined the effect of maternal swimming on the mouse offspring's neurogenesis. Our data demonstrate decreased proliferation in sublayers of the postnatal dentate gyrus in offspring of swimming mother at postnatal day (P) 8 accompanied with decreased survival of newly generated cells 4 weeks later. The reduction in cell numbers was predominantly seen in the hilus and molecular layer. At P35, the reduced amount of cells was also reflected by a decrease in the population of newly generated immature and mature neurons of the granule cell layer. Our data suggest that forced maternal swimming at high-intensity has a negative effect on the neurogenic niche development in postnatal offspring.

The ACTN3 R577X polymorphism affects the lipid profile and the prognosis of nutritional intervention in HIV-positive patients.

The hypothesis of the present study is that the polymorphisms in the APOC3, CEPT, ACE, and ACTN3 genes can affect the outcome of nutritional intervention and the plasma lipid profile of HIV+ patients. To test the hypothesis, genetic material was collected from buccal cells, and serum was collected for biochemical analysis. Sixty-five patients were analyzed. The incorporation of protease inhibitor (PI) was more frequent in women (77% vs 33% in men). Nutritional intervention improved anthropometric parameters independent of the genotype. Patients with the RR genotype for the ACTN3 R577X polymorphism had lower glycemia (RR = 95.4 ± 6.5 mg/dL, RX = 102.6 ± 10.6 mg/dL, XX = 110.1 ± 16.3 mg/dL; P = .03) and a greater reduction in low-density lipoproteins (LDL) after intervention (LDL: RR = -23.7 ± 15.8 mg/dL, RX = 1.32 ± 5.13 mg/dL, XX = 30.21 ± 24.4 mg/dL; P = .01). Patients using PI had a negative response to dietary intervention regarding the levels of high-density lipoprotein (-2.4 ± 1.70 with PI, 2.56 ± 1.60 mg/dL without PI; P = .02), very low density lipoprotein (0.84 ± 2.73 with IP, -5.46 ± 3.37 mg/dL without PI; P = .03), and triglycerides (1.79 ± 13.22 with PI, -34.00 ± 17.67 mg/dL without PI; P = .052). This response was also independent of the genotype (P > 0.05) and suggested the need for oral lipid-lowering drugs in all HIV+ patients using PI. Our results indicate that the ACTN3 R577X polymorphism is a good predictor of both the lipid profile and the prognosis of nutritional intervention in reducing LDL in HIV+ patients.

Deletion of Kinin B2 Receptor Alters Muscle Metabolism and Exercise Performance.

Metabolic syndrome is a cluster of metabolic risk factors such as obesity, diabetes and cardiovascular diseases. Mitochondria is the main site of ATP production and its dysfunction leads to decreased oxidative phosphorylation, resulting in lipid accumulation and insulin resistance. Our group has demonstrated that kinins can modulate glucose and lipid metabolism as well as skeletal muscle mass. By using B2 receptor knockout mice (B2R-/-) we investigated whether kinin action affects weight gain and physical performance of the animals. Our results show that B2R-/- mice are resistant to high fat diet-induced obesity, have higher glucose tolerance as well as increased mitochondrial mass. These features are accompanied by higher energy expenditure and a lower feed efficiency associated with an increase in the proportion of type I fibers and intermediary fibers characterized by higher mitochondrial content and increased expression of genes related to oxidative metabolism. Additionally, the increased percentage of oxidative skeletal muscle fibers and mitochondrial apparatus in B2R-/- mice is coupled with a higher aerobic exercise performance. Taken together, our data give support to the involvement of kinins in skeletal muscle fiber type distribution and muscle metabolism, which ultimately protects against fat-induced obesity and improves aerobic exercise performance.

Modification of epigenetic patterns in low birth weight children: importance of hypomethylation of the ACE gene promoter.

There is a growing body of evidence that epigenetic alterations are involved in the pathological mechanisms of many chronic disorders linked to fetal programming. Angiotensin-converting enzyme (ACE) appears as one candidate gene that brings new insights into the epigenetic control and later development of diseases. In this view, we have postulated that epigenetic modifications in the ACE gene might show different interactions between birth weight (BW), blood pressure levels, plasma ACE activity and ACE I/D polymorphism. To explore this hypothesis, we performed a cross-sectional study to evaluate the DNA methylation of 3 CpG sites using pyrosequencing within the ACE gene promoter of peripheral blood leukocytes from 45 LBW children compared with 70 NBW children. Our results have revealed that LBW children have lower methylation levels (P<0.001) in parallel with a higher ACE activity (P = 0.001). Adjusting for prematurity, gender, age, body mass index, and family history of cardiovascular disease did not alter these findings. We have also performed analyses of individual CpG sites. The frequency of DNA methylation was significantly different at two CpG sites (site 1: nucleotide position +555; and site 3: nucleotide position +563). In addition, we have found a significant inverse correlation between degree of DNA methylation and both ACE activity (P<0.001) and systolic blood pressure levels (P<0.001). We also observed that the methylation level was significantly lower in LBW children who are carriers of the DD genotype compared to NBW children with DD genotype (P<0.024). In conclusion, we are able to demonstrate that the hypomethylation in the 3 CpG sites of ACE gene promoter is associated with LBW in 6 to 12 year-old children. The magnitude of these epigenetic changes appears to be clinically important, which is supported by the observation that discrete changes in DNA methylation can affect systolic blood pressure and ACE protein activity levels.

Lymphocyte glucose and glutamine metabolism as targets of the anti-inflammatory and immunomodulatory effects of exercise.

Glucose and glutamine are important energetic and biosynthetic nutrients for T and B lymphocytes. These cells consume both nutrients at high rates in a function-dependent manner. In other words, the pathways that control lymphocyte function and survival directly control the glucose and glutamine metabolic pathways. Therefore, lymphocytes in different functional states reprogram their glucose and glutamine metabolism to balance their requirement for ATP and macromolecule production. The tight association between metabolism and function in these cells was suggested to introduce the possibility of several pathologies resulting from the inability of lymphocytes to meet their nutrient demands under a given condition. In fact, disruptions in lymphocyte metabolism and function have been observed in different inflammatory, metabolic, and autoimmune pathologies. Regular physical exercise and physical activity offer protection against several chronic pathologies, and this benefit has been associated with the anti-inflammatory and immunomodulatory effects of exercise/physical activity. Chronic exercise induces changes in lymphocyte functionality and substrate metabolism. In the present review, we discuss whether the beneficial effects of exercise on lymphocyte function in health and disease are associated with modulation of the glucose and glutamine metabolic pathways.

Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury.

Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1ß and TNF-α). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy.

Kinin B1 receptor deficiency attenuates cisplatin-induced acute kidney injury by modulating immune cell migration.

UNLABELLED: Cisplatin is a chemotherapeutic agent that causes severe renal dysfunction. The kinin B1 receptor has been associated with the migration of immune cells to injured tissue as well as with renal inflammation. To examine the role of the kinin B1 receptor in cisplatin-induced acute kidney injury, we used kinin B1 receptor knockout mice and treatment with a receptor antagonist before and after cisplatin administration. Cisplatin injection caused exacerbation of renal macrophage and neutrophil migration, higher levels of serum creatinine and blood urea, upregulation of B1 receptor mRNA and an increase in pro-inflammatory cytokines expression. B1 receptor knockout mice exhibited a reduction in serum creatinine and blood urea levels, diminished apoptosis, and decreased cisplatin-induced upregulation of inflammatory components. Moreover, treatment with the B1 receptor antagonist prior to cisplatin administration normalized serum creatinine, blood urea levels, protected from acute tubular necrosis, apoptosis-related genes, and prevented upregulation of pro-inflammatory cytokines. Thus, we propose that kinins have an important role in cisplatin-induced acute kidney injury by impairing immune cells migration to renal tissue during cisplatin nephrotoxicity. KEY MESSAGE: Kinin B1 receptor is upregulated after cisplatin exposure. Kinin B1 receptor deficiency diminishes the nephrotoxicity caused by cisplatin. Kinin B1 receptor deficiency ameliorates the inflammatory response. Kinin B1 receptor deficiency diminishes apoptosis caused by cisplatin. Kinin B1 receptor antagonism ameliorates renal function after cisplatin injection.