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Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts.
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ABSTRACT: Sepsis is the most frequent risk factor for acute kidney injury (AKI) in critically ill infants. Sepsis-induced dysregulation of kidney microcirculation in newborns is unresolved. The objective of this study was to use the translational swine model to evaluate changes in kidney function during the early phase of sepsis in newborns and the impact of fluid plus norepinephrine resuscitation. Newborn pigs (3-7-day-old) were allocated randomly to three groups: 1) sham, 2) sepsis (cecal ligation and puncture) without subsequent resuscitation, and 3) sepsis with lactated Ringer plus norepinephrine resuscitation. All animals underwent standard anesthesia and mechanical ventilation. Cardiac output and glomerular filtration rate were measured noninvasively. Mean arterial pressure, total renal blood flow, cortical perfusion, medullary perfusion, and medullary tissue oxygen tension (mtPO 2 ) were determined for 12 h. Cecal ligation and puncture decreased mean arterial pressure and cardiac output by more than 50%, with a proportional increase in renal vascular resistance and a 60-80% reduction in renal blood flow, cortical perfusion, medullary perfusion, and mtPO 2 compared to sham. Cecal ligation and puncture also decreased glomerular filtration rate by ~79% and increased AKI biomarkers. Isolated foci of tubular necrosis were observed in the septic piglets. Except for mtPO 2 , changes in all these parameters were ameliorated in resuscitated piglets. Resuscitation also attenuated sepsis-induced increases in the levels of plasma C-reactive protein, proinflammatory cytokines, lactate dehydrogenase, alanine transaminase, aspartate aminotransferase, and renal NLRP3 inflammasome. These data suggest that newborn pigs subjected to cecal ligation and puncture develop hypodynamic septic AKI. Early implementation of resuscitation lessens the degree of inflammation, AKI, and liver injury.
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Injúria Renal Aguda , Animais Recém-Nascidos , Hidratação , Norepinefrina , Ressuscitação , Sepse , Animais , Suínos , Sepse/terapia , Sepse/fisiopatologia , Ressuscitação/métodos , Hidratação/métodos , Injúria Renal Aguda/terapia , Injúria Renal Aguda/metabolismo , Inflamação , Rim/metabolismo , Circulação Renal , Taxa de Filtração GlomerularRESUMO
Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT1-5-HT7), with 5-HT2 predominantly mediating renal vasoconstriction. Cyclooxygenase (COX) and smooth muscle intracellular Ca2+ levels ([Ca2+]i) have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. In the present study, we demonstrate that 5-HT stimulated human TRPV4 transiently expressed in Chinese hamster ovary cells. 5-HT2A is the predominant 5-HT2 receptor subtype in freshly isolated neonatal pig renal microvascular smooth muscle cells (SMCs). HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in the SMCs. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca2+]i and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transdermal measurement of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC and 5-HT2 receptor antagonist ritanserin attenuated 5-HT effects on RBF, RVR, and GFR. Moreover, the serum and urinary COX-1 and COX-2 levels in 5-HT-treated piglets were unchanged compared with the control. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production.
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Músculo Liso Vascular , Serotonina , Recém-Nascido , Cricetinae , Animais , Humanos , Suínos , Músculo Liso Vascular/metabolismo , Canais de Cátion TRPV/metabolismo , Células CHO , Cricetulus , Rim/irrigação sanguínea , Receptores de Serotonina/metabolismoRESUMO
Transdermal measurement of glomerular filtration rate (GFR) has been used to evaluate kidney function in conscious animals. This technique is well established in rodents to study acute kidney injury and chronic kidney disease. However, GFR measurement using the transdermal system has not been validated in pigs, a species with a similar renal system to humans. Hence, we investigated the effect of sepsis on transdermal GFR in anesthetized and mechanically ventilated neonatal pigs. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP). The transdermal GFR measurement system consisting of a miniaturized fluorescence sensor was attached to the pig's shaved skin to determine the clearance of fluorescein-isothiocyanate (FITC) conjugated sinistrin, an intravenously injected GFR tracer. Our results show that at 12 h post-CLP, serum creatinine increased with a decrease in GFR. This study demonstrates, for the first time, the utility of the transdermal GFR approach in determining renal function in mechanically ventilated, neonatal pigs.
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Respiração Artificial , Sepse , Animais , Creatinina , Fluoresceína-5-Isotiocianato , Fluoresceínas , Taxa de Filtração Glomerular , Humanos , Recém-Nascido , Rim , Oligossacarídeos , SuínosRESUMO
Context: Studies have shown that cardiac triglyceride accumulation and impaired Na+-K+-ATPase activity are linked to diabetes- related cardiovascular disease, particularly in women.Objectives: We hypothesised that allopurinol (ALL) and valproic acid (VPA) treatment would improve cardiac triglyceride and Na+-K+-ATPase activity independent of circulating aldosterone in Combined Oral Contraceptive (COC)-induced dysglycemiaMaterials and methods: Rats received COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel; po) with or without ALL (1 mg; po) and VPA (20 mg; po) for 6 weeks.Results: COC-treatment led to impaired glucose tolerance, accumulated abdominal fat, dyslipidemia, elevated plasma MDA, PAI-1 and aldosterone levels and also reduced plasma nitric oxide bioavailability and cardiac Na+-K+-ATPase activity. However, either ALL or VPA treatment ameliorated these alterations comparably independent of elevated aldosterone levelDiscussion and conclusion: Our results suggest that either ALL or VPA would improve cardiac TG and Na+-K+-ATPase activity comparably in COC-treated rats, regardless of circulating aldosterone level.
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Intolerância à Glucose , Resistência à Insulina , Adenosina Trifosfatases , Aldosterona , Alopurinol/farmacologia , Animais , Anticoncepcionais Orais Combinados , Feminino , Humanos , Levanogestrel , Óxido Nítrico , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio , Triglicerídeos , Ácido Valproico/farmacologiaRESUMO
Lead acetate associated tissue injury has been linked to altered antioxidant defenses, hyperuricemia and inflammation. We hypothesized that watermelon rind extract, would ameliorate lead acetate-induced hepato-renal injury. Thirty Male Wistar rats received distilled water, lead acetate (Pb; 5 mg/kg) with or without watermelon rind extract (WM; 400 mg/kg; WM + Pb; 15 days of WM pretreatment); Pb + WM (15 days of WM post treatment) and simultaneous treatment (WM-Pb) for 30 days. Lead toxicity led to elevated serum malondialdehyde, creatinine, urea, uric acid, lactate dehydrogenase, liver injury enzymes, as well as decreased body weight. Decreased serum levels of reduced glutathione, nitric oxide, total protein and glutathione peroxidase activity was also observed. However, these alterations were ameliorated by watermelon rind extract in lead acetate-treated rats. Watermelon rind ethanol extract protects against lead acetate-induced hepato-renal injury through improved antioxidant defenses at least in part, via uric acid/nitric oxide-dependent pathway signifying the health benefits of this agricultural waste and a potential for waste recycling while limiting environmental pollution.
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AIM: Environmental pollutants such as plastic-component substances (phthalates and bisphenol A) that coexist in natural ecosystems have been linked to an increase in the occurrence of human health hazards, particularly cardiovascular health. This study was designed to investigate single and combined cardio-toxic effects of dibutyl phthalate and bisphenol-A and the possible interventional role of rutin. MATERIALS AND METHODS: Forty-two rats were randomized into 7 groups of 6 animals each and were treated as follows for 28 days: Control (0.1% DMSO), Bisphenol-A (BPA, 25 mg/kg, p.o), Dibutyl phthalate (DBP, 25 mg/kg, p.o), BPA + Rutin (25 mg/kg, Rt 50 mg/kg), DBP + Rt (25 mg/kg, Rt 50 mg/kg), BPA + DBP, BPA + DBP + Rt. Cardiac lipid peroxidation, antioxidants and inflammatory markers activities were measured. KEY FINDINGS: The result showed that BPA reduced the superoxide dismutase (SOD) activity, DBP and DBP+ BPA reduced the catalase (CAT) activity, DBP reduced glutathione (GSH) and nuclear factor erythroid 2-related factor 2 (Nrf2) while malondialdehyde (MDA) increased in DBP + BPA group. Also, DBP increased tissue C-reactive protein (CRP); DBP, DBP + BPA increased tissue nuclear factor kappa B (NF-κB); DBP + BPA increased plasma CRP; BPA increased plasma NF-κB. However, rutin efficiently reduced MDA level, CRP and NF-κB; increasing SOD, GSH and Nrf2 levels in DBP and BPA exposed rats. SIGNIFICANCE: These results revealed that bisphenol and dibutyl phthalate exposure caused oxidative stress and inflammation in the heart through Nrf2/NF-κB signaling pathway while oral administration of rutin prevents these effects via upregulation of Nrf2 and suppression of NF-κB signaling pathway.
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Compostos Benzidrílicos/toxicidade , Dibutilftalato/toxicidade , Inflamação/patologia , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Fenóis/toxicidade , Rutina/farmacologia , Animais , Creatina Quinase/sangue , Inflamação/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Troponina I/sangueRESUMO
CONTEXT: Suppressed glucose metabolism, elevated fatty acid metabolism and lipid deposition within myocardial cells are the key pathological features of diabetic cardiomyopathy. Studies have associated cadmium exposure with metabolic disturbances. OBJECTIVE: To examine the effects of cadmium exposure on cardiac glucose homeostasis and lipid accumulation in male Wistar rats. METHODS: Male Wistar rats were treated for 21 days as (n = 5): Control, cadmium chloride Cd5 (5 mg/kg, p.o.), cadmium chloride Cd30 (30 mg/kg, p.o). RESULTS: The fasting serum insulin level in this study decreased significantly. Pyruvate and hexokinase activity reduced significantly in the Cd5 group while no significant change in lactate and glycogen levels. The activity of pyruvate dehydrogenase enzyme significantly increased with an increasing dosage of cadmium. The free fatty acid, total cholesterol and triglyceride levels in the heart increased significantly with increasing dosage of cadmium when compared with the control. Lipoprotein lipase activity in the heart showed no difference in the Cd5 group but a reduction in the activity in the Cd30 group was observed. CONCLUSION: This study indicates that cadmium exposure interferes with cardiac substrate handling resulting in impaired glucometabolic regulation and lipid accumulation which could reduce cardiac efficiency.
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Cloreto de Cádmio , Cádmio/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Cádmio/sangue , Teste de Tolerância a Glucose , Humanos , Insulina/análise , Lipídeos , Masculino , Oxirredutases , Piruvatos , Ratos , Ratos WistarRESUMO
Impaired renal function is a common complication of diabetes mellitus (DM) that often degenerates to cardiovascular disease, contributing to high morbidity and reduced survival worldwide. Short chain fatty acids (SCFAs), including acetate has shown potential benefits in glycemic or metabolic regulation but its effect on diabetes-associated renal toxicity/impairment is not clear. Herein, we investigated the hypothesis that acetate would ameliorate renal toxicity, accompanying DM, possibly by suppression of xanthine oxidase (XO) activity. Adult male Wistar rats (230-260 g) were allotted into groups (n = 6/group) namely: control (vehicle; po), sodium acetate (NaAc)-treated (200 mg/kg), diabetic with or without NaAc groups. DM was induced by intraperitoneal injection of streptozotocin 65 mg/kg after a dose of nicotinamide (110 mg/kg). Diabetic animals showed increased fasting glucose and insulin, renal triglyceride, total cholesterol, atherogenic lipid, malondialdehyde, XO, tissue necrosis factor-α, uric acid, interleukin-6, aspartate transaminase/alanine aminotransferase ratio, gamma-glutamyl transferase and decreased glutathione and nitric oxide concentration. The renal tissue was characterized with disrupted tissue architecture, enlarged Bowman's space, congested glomeruli and adherence of abnormal segments of tuft to Bowman's capsule with consequent elevated serum creatinine and urea concentration. However, these alterations were attenuated by NaAc. The study demonstrates that acetate ameliorates diabetes-induced nephrotoxicity, which is associated with suppressed XO and its accompanied pro-inflammatory mediators. Therefore, SCFAs, acetate would be a promising dietary-derived therapeutic agent for the prevention and management of diabetes-associated renal disturbances.
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Diabetes Mellitus Experimental/patologia , Rim/enzimologia , Rim/patologia , Acetato de Sódio/farmacologia , Xantina Oxidase/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Aterosclerose/sangue , Aterosclerose/complicações , Glicemia/metabolismo , Colesterol/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Jejum/sangue , Glutationa/metabolismo , Mediadores da Inflamação/metabolismo , Insulina/sangue , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Modelos Biológicos , Niacinamida , Óxido Nítrico/metabolismo , Ratos Wistar , Estreptozocina , Triglicerídeos/metabolismoRESUMO
High fat diet (HFD) is a risk factor for metabolic syndrome which is characterized by overt glucose dysmetabolism and tissue derangement. The liver and pancreas are important metabolic tissues with anatomical proximity sharing splanchnic and mesenteric circulation but it is unclear whether, there is an associated metabolic status between the two organs in health and disease. Uric acid (UA) hypersecretion and ectopic lipid accumulation are characteristic pathophysiology of an array of non-communicable diseases. Sodium butyrate (BUT) is reputed for therapeutic roles in metabolic derangement. Therefore, the present study investigated synchrony in hepatic and pancreatic UA and lipid metabolic status in HFD-induced glucose dysregulation and probed the beneficial effects of BUT. Twenty-four female Wistar rats were treated with normal rat chow and distilled water (po) or sodium butyrate (200 mg/kg; po) or high fat diet and distilled water (po) or high fat diet and sodium butyrate. Results showed that HFD increased plasma, pancreatic and hepatic triglyceride, triglyceride-glucose index, malondialdehyde, uric acid (UA), lactate dehydrogenase but reduced glucose-6-phosphate dehydrogenase. Histological analysis revealed hepatic and pancreatic architectural derangement and cellular degeneration in HFD-fed animals. However, BUT reversed the HFD-induced systemic, pancreatic and hepatic synchronous dysmetabolism with evidence of improved histology. HFD-induced lipid and UA alterations were synchronous in the pancreas and liver. BUT elicits beneficial effects on systemic and tissue HFD-induced deleterious metabolic changes which were synchronized in pancreas and liver of rats.
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Ácido Butírico/farmacologia , Dislipidemias/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Pâncreas/efeitos dos fármacos , Ácido Úrico/sangue , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/etiologia , Dislipidemias/patologia , Feminino , Transtornos do Metabolismo de Glucose/sangue , Transtornos do Metabolismo de Glucose/tratamento farmacológico , Transtornos do Metabolismo de Glucose/etiologia , Hiperuricemia/sangue , Hiperuricemia/etiologia , Hiperuricemia/patologia , Hipoglicemiantes/farmacologia , Fígado/metabolismo , Fígado/patologia , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Síndrome Metabólica/patologia , Pâncreas/metabolismo , Pâncreas/patologia , Ratos WistarRESUMO
Polycystic ovarian syndrome (PCOS) is a complex endocrine disease among women of reproductive age and is one of the main causes of infertility. Non-alcoholic fatty liver disease (NAFLD), the most prominent chronic liver disease in adults, is characterized by excess hepatic triglyceride (TG) accumulation. PCOS women have increased risk of NAFLD and uric acid has been documented to have a positive correlation with subclinical tissue damage and might be the link in the cystic. Spironolactone (SPL) is a mineralocorticoid receptor (MR) blocker that has been in wide clinical use for some decades. In this research, we investigated the effects of SPL on ovarian and hepatic tissue damage in experimental PCOS rats induced by letrozole (LET). A total of eighteen adult female Wistar rats were used for this study and the animals divided into 3 groups are treated with vehicle, LET (1 mg/kg), and LET+SPL (SPL; 0.25 mg/kg), p.o. once daily respectively for 21 uninterrupted days. Results showed that LET treatment induced features of PCOS characterized by increased plasma testosterone (T) and luteinizing hormone (LH) together with increased body weight. Abnormal ovarian and hepatic histomorphological changes were also observed with elevated uric acid (UA) and TG accumulation in both tissues respectively. Treatment with SPL however attenuated the elevated testosterone in the LET-induced PCOS model accompanied with a reversal in the observed ovarian and hepatic UA, TG accumulation, and altered histomorphological changes. Taken together, spironolactone reversed the PCOS-induced ovarian and hepatic tissue damage by suppressing tissue UA and TG accumulation.
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Letrozol/toxicidade , Fígado/efeitos dos fármacos , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/metabolismo , Espironolactona/farmacologia , Triglicerídeos/metabolismo , Ácido Úrico/metabolismo , Animais , Feminino , Fígado/metabolismo , Fígado/patologia , Ovário/metabolismo , Ovário/patologia , Síndrome do Ovário Policístico/induzido quimicamente , Ratos , Ratos WistarRESUMO
Reduced liver glycogen synthesis might signify increased glucose flux towards fat synthesis and triggers hepatic triglyceride accumulation and dysmetabolism. Adenosine deaminase (ADA) reduces adenosine content which increases glycogenolysis. In the present study, we evaluate the effect of modulating glycogen synthesis and ADA by lithium chloride (LiCl) on nicotine-induced dysmetabolism. Twenty four male Wistar rats (n = 6/group) were allotted into four groups namely; vehicle-treated (po), nicotine-treated (1.0 mg/kg; po), LiCl-treated (5.0 mg/kg; po) and nicotine + LiCl-treated groups. The treatments lasted for 8 weeks. Nicotine exposure resulted in reduced body weight gain, liver weight, visceral adiposity, glycogen content and synthase. Along with increased insulin resistance (IR), fasting plasma glucose, lactate, plasma and hepatic ADA, XO, UA, and triglyceride (TG), total cholesterol (TC), free fatty acid, lipid peroxidation and liver injury markers. However, plasma and hepatic glucose-6-phosphate dehydrogenase-dependent antioxidant defenses were not affected by nicotine exposure. Concurrent treatment with LiCl normalizes all alterations with exception of hepatic TC. This result shows that enhancement of hepatic glycogen synthesis and suppression of ADA/XO/uric acid pathway by lithium can salvage the liver from nicotine-induced TG accumulation.
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Adenosina Desaminase/metabolismo , Lítio/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Nicotina/farmacologia , Triglicerídeos/metabolismo , Animais , Antioxidantes/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Glicogenólise/efeitos dos fármacos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Glicogênio Hepático/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-ß, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17ß-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.
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Estrogênios/sangue , Resistência à Insulina/fisiologia , Obesidade/sangue , Obesidade/tratamento farmacológico , Ovariectomia , Espironolactona/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Mediadores da Inflamação/sangue , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Ovariectomia/efeitos adversos , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Gestational glucocorticoid (GC) treatment has been associated with cardiometabolic disorder (CMD) in offspring's in later life. Elevated dipeptidyl peptidase-4 (DPP-4) activity, endoglin and glycogen synthase kinase-3 (GSK-3) has also been implicated in the development of insulin resistance (IR) and/or vascular inflammation. We aimed to investigate the impact of GC exposure on glucose metabolism and the circulating levels of inflammatory biomarkers, DPP-4 activity and GSK-3 in pregnant rats. Pregnant Wistar rats received either vehicle or dexamethasone (DEX; 0.2â¯mg/kg; po) between gestational days 14 and 19. Gestational GC exposure resulted in impaired glucose homeostasis that is accompanied with elevated circulating levels of inflammatory biomarkers (endoglin, uric acid, and platelet/lymphocyte ratio), oxidative stress (malondialdehyde), blood viscosity, reduced NO level and increased DPP-4 activity. However, these effects were associated with atherogenic dyslipidemia and reduced GSK-3.We conclude that plasma endoglin, a marker of vascular inflammation, and plasma DPP-4 activity are increased in pregnant rats treated with GC during late gestation. Therefore, glucose deregulation associated with gestational GC exposure is through endoglin-/DPP-4-dependent but GSK-3-independent pathway.
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Glicemia/metabolismo , Dipeptidil Peptidase 4/sangue , Endoglina/sangue , Glucocorticoides/toxicidade , Animais , Dexametasona/toxicidade , Dislipidemias/sangue , Dislipidemias/induzido quimicamente , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Exposição Materna/efeitos adversos , Gravidez , Ratos , Ratos WistarRESUMO
CONTEXT: Cigarette smoking is considered to be a major risk factor for the development of diabetes and cardiovascular disease. Oestrogen-progestin combined oral contraceptive (COC) use has been associated with adverse cardiometabolic events. OBJECTIVE: We hypothesized that nicotine would ameliorate insulin resistance (IR) that is accompanied by decreased cardiac glycogen synthase kinase-3 (GSK-3) and plasminogen activator inhibitor-1 (PAI-1). METHODS: Female Wistar rats received (po) low-(0.1 mg/kg) or high-nicotine (1.0 mg/kg) with or without COC containing 5.0 µg levonorgestrel plus 1.0 µg ethinylestradiol daily for 8 weeks. RESULTS: Data showed that COC treatment or nicotine exposure led to IR, glucose deregulation, atherogenic dyslipidemia, increased corticosterone, aldosterone, cardiac and circulating GSK-3 values and PAI-1. However, these effects with the exception of corticosterone and aldosterone were ameliorated in COC + nicotine-exposed rats. CONCLUSION: Amelioration of IR induced by COC treatment is accompanied by decreased circulating PAI-1, cardiac PAI-1 and GSK-3 instead of circulating aldosterone and corticosterone.
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Anticoncepcionais Orais Combinados/efeitos adversos , Etinilestradiol/efeitos adversos , Quinase 3 da Glicogênio Sintase/metabolismo , Coração/efeitos dos fármacos , Resistência à Insulina , Levanogestrel/efeitos adversos , Nicotina/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Administração Oral , Aldosterona/sangue , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , Anticoncepcionais Orais Combinados/antagonistas & inibidores , Corticosterona/sangue , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Etinilestradiol/antagonistas & inibidores , Feminino , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/sangue , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Levanogestrel/antagonistas & inibidores , Miocárdio/enzimologia , Miocárdio/metabolismo , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/química , Estado Pré-Diabético/induzido quimicamente , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Estado Pré-Diabético/prevenção & controle , Distribuição Aleatória , Ratos WistarRESUMO
Estrogen-progestin oral contraceptives (COC) or tobacco smoking has been associated with hypertension and endothelial dysfunction resulting in increased risk of cardiovascular diseases (CVD). Contrasting effects of nicotine exposure on endothelial function have been reported. The effect of non-smoking nicotine exposure on endothelial dysfunction during COC treatment remains to be fully elucidated. We therefore, sought to determine the effects of nicotine exposure during COC treatment on endothelial dysfunction mediators and circulating corticosteroids. Female Wistar rats aged 10 weeks were given (po) vehicle, nicotine (1.0 mg/kg) with or without COC steroids (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) daily for 6 weeks. Nicotine exposure caused 113.3% increase in insulinemia whereas COC treatment led to 76.9% increased insulinemia compared with control. Furthermore, COC treatment or nicotine exposure led to glucose deregulation, insulin resistance, reduced nitric oxide bioavailability, elevated plasminogen activator inhibitor-1, uric acid, oxidative stress, atherogenic dyslipidemia, and corticosteroids. However, COC + NIC treatment led to 41.2% decrease in insulemina compared with COC-treated rats. Furthermore, all other alterations were alleviated by nicotine exposure in COC-treated female rats with the exception of corticosteroids.