RESUMO
Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering agents widely used for the treatment of type 2 diabetes mellitus. A number of clinical trials in type 2 diabetic patients with different degrees of renal impairment have clearly demonstrated that SGLT2 inhibitors reduce the progression rate of diabetic kidney disease. Furthermore, recent studies have shown that SGLT2 inhibitors also exert a protective effect in the case of non-diabetic kidney disease. Consequently, it has been hypothesized that the nephroprotective activity of these drugs could exceed the canonical impact on glycemic control and that the resulting beneficial effects could be the consequence of their pleiotropic properties (proven reduction of inflammation, fibrosis, oxidative stress and sympathetic nervous activity) both at systemic and tissue levels, suggesting that the efficacy of these drugs could also be extended to non-diabetic nephropathies. This review focuses on the nephroprotective effects of SGLT2 inhibitors in different experimental models of non-diabetic kidney disease. The different glucose-independent mechanisms potentially implemented by SGLT2 inhibitors to ultimately protect the non-diabetic kidney are described in detail, and conflicting results, when present, are discussed.
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The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.
Assuntos
Hipertensão , Inibidores do Transportador 2 de Sódio-Glicose , Ratos , Animais , Angiotensina II/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio , Glicemia , Tirosina 3-Mono-Oxigenase/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Cardiomegalia , Pressão Sanguínea , Inflamação/tratamento farmacológico , FibroseRESUMO
A link between hypertension and long-term bone health has been suggested. The aim of this study was to investigate the effects of chronic angiotensin II administration on urinary calcium/phosphate excretion, bone mineral density, bone remodeling and osteoblast population in a well-established experimental model of hypertension, in the absence of possible confounding factors that could affect bone metabolism. Male Sprague-Dawley rats, divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis, n = 8); (b) Ang II+losartan (Los, 50 mg/kg/day, per os, n = 6); (c) control group (physiological saline, sub cutis, n = 9); and (d) control+losartan (n = 6) were treated for four weeks. During the experimental period, 24-hour diuresis, urinary calcium, phosphate and sodium excretion were measured prior to the treatment, at two weeks of treatment, and at the end of the treatment. Systolic blood pressure was measured by plethysmography technique (tail cuff method). At the end of the experimental protocol, the rats were euthanized and peripheral quantitative computed tomography at the proximal metaphysis and at the diaphysis of the tibiae and quantitative bone histomorphometry on distal femora were performed. Angiotensin II-dependent hypertension is associated with increased calcium and phosphate excretion. AT1 receptor blockade prevented the increase of blood pressure and phosphate excretion but did not affect the increase of calcium excretion. These changes took place without significantly affecting bone density, bone histology or osteoblast population. In conclusion, in our experimental conditions, angiotensin II-dependent hypertension gave rise to an increased urinary excretion of calcium and phosphate without affecting bone density.
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Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 µg/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure.
Assuntos
Angiotensina II/administração & dosagem , Angiotensina I/administração & dosagem , Cardiomegalia/prevenção & controle , Hipertensão/tratamento farmacológico , Imidazóis/administração & dosagem , Losartan/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Fibrose , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Imidazóis/farmacologia , Injeções Intraperitoneais , Losartan/farmacologia , Masculino , Fragmentos de Peptídeos/farmacologia , Proto-Oncogene Mas/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, are nephroprotective in case of diabetes, but whether a similar beneficial effect may be detectable also in case of chronic non-diabetic kidney diseases remains still unknown. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, on the progression of cyclosporine nephropathy, in the absence of diabetes. METHODS: Sprague Dawley rats (n = 27) have been fed with low-salt diet starting 10 days before the beginning and finished at the end of the experimental period. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection, n = 8) and CsA plus empagliflozin (Empa, 10 mg/kg/day, per os, n = 7) were administered for 4 weeks. The control groups were treated with placebo (Control, n = 7) or empagliflozin (Control + Empa, n = 5). Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental period. At the end of the experimental protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages), type I and type IV collagen expression, and tyrosine hydroxylase expression, used as marker of sympathetic nerve activity. RESULTS: CsA-treated rats showed a significant increase (p < 0.01) in blood pressure, which was reduced by administration of empagliflozin (p < 0.05). CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p < 0.05), renal inflammatory infiltrates (p < 0.05), type I and type IV collagen expression (p < 0.01), and tyrosine hydroxylase expression (p < 0.01) as compared to the control rats and control + Empa-treated rats. Treatment with empagliflozin in CsA-treated rats reduced glomerular (p < 0.01) and tubulo-interstitial fibrosis (p < 0.05), type I and type IV collagen expression (p < 0.01), inflammatory cell infiltration (p < 0.01) and tyrosine hydroxylase expression (p < 0.05), as compared to rats treated with CsA. CONCLUSION: Empagliflozin administration caused a reduction in blood pressure in CsA-treated rats and showed a protective effect on CsA nephropathy by decreasing renal fibrosis, type I and type IV collagen expression, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that empagliflozin promotes nephroprotection also in non-diabetic kidney disease.
Assuntos
Ciclosporina/administração & dosagem , Nefropatias/prevenção & controle , Rim/patologia , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Animais , Compostos Benzidrílicos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Fibrose , Glucosídeos/administração & dosagem , Nefropatias/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio/fisiologiaRESUMO
CONTEXT: Insulin resistance and diabetes may influence separately or in combination whole body energy metabolism. OBJECTIVE: To assess the impact of insulin resistance and/or overt type 2 diabetes on resting energy expenditure (REE) in class 3 obese individuals. DESIGN AND SETTING: Retrospective, cross-sectional analysis of a set of data about individuals attending the outpatients service of a single center of bariatric surgery between January 2015 and December 2017. PATIENTS: We screened 382 patients in which abnormal thyroid function was excluded, and segregated them in three groups of subjects: patients with type 2 diabetes (T2DM; n=70), non-diabetic insulin-resistant patients with HOMA-IR ≥ 3 (n=236), non-diabetic insulin-sensitive patients with HOMA-IR < 3 (n=75). MAIN OUTCOME MEASURE: Resting energy expenditure (REE), body composition and insulin resistance assessed using indirect calorimetry, bioimpedance and HOMA-IR. RESULTS: Non-diabetic insulin-sensitive patients resulted to be younger, with lower BMI and higher prevalence of female subjects; meanwhile, non-diabetic but insulin-resistant patients and T2DM patients were not different in terms of anthropometric parameters. REE was higher in T2DM than in non-diabetic insulin-resistant and insulin-sensitive individuals when expressed as percent of the predicted REE (based on Harris Benedict equation) (p<0.0001) or when adjusted for kg of free fat mass (p<0.0001) and was found to be higher also in insulin-resistant vs insulin-sensitive patients (p<0.001). The respiratory quotient was different between groups (0.87±0.11, 0.86±0.12 and 0.91±0.14 in T2DM, insulin-resistant and insulin-sensitive patients, respectively; p<0.03). Regression analysis confirmed that HOMA-IR was independently associated with the REE (R2=0.110, p<0.001). CONCLUSION: Class 3 obese patients with normal insulin sensitivity are characterized by reduced fasting REE in comparison to insulin-resistant obese patients and obese patients with short duration of diabetes supporting the hypothesis that down-regulation of nutrients' oxidative disposal may represent an adaptation of energy metabolism in obese individuals with preserved insulin sensitivity.
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CONTEXT: Growing evidence suggests that appropriate levothyroxine (LT4) replacement therapy may not correct the full set of metabolic defects afflicting individuals with hypothyroidism. OBJECTIVE: To assess whether obese subjects with primary hypothyroidism are characterized by alterations of the resting energy expenditure (REE). DESIGN: Retrospective analysis of a set of data about obese women attending the outpatients service of a single obesity center from January 2013 to July 2019. PATIENTS: A total of 649 nondiabetic women with body mass index (BMI)â >â 30 kg/m2 and thyrotropin (TSH) level 0.4-4.0 mU/L were segregated into 2 groups: patients with primary hypothyroidism taking LT4 therapy (nâ =â 85) and patients with normal thyroid function (nâ =â 564). MAIN OUTCOMES: REE and body composition assessed using indirect calorimetry and bioimpedance. RESULTS: REE was reduced in women with hypothyroidism in LT4 therapy when compared with controls (28.59â ±â 3.26 vs 29.91â ±â 3.59 kcal/kg fat-free mass (FFM)/day), including when adjusted for age, BMI, body composition, and level of physical activity (Pâ =â 0.008). This metabolic difference was attenuated only when adjustment for homeostatic model assessment of insulin resistance (HOMA-IR) was performed. CONCLUSIONS: This study demonstrated that obese hypothyroid women in LT4 therapy, with normal serum TSH level compared with euthyroid controls, are characterized by reduced REE, in line with the hypothesis that standard LT4 replacement therapy may not fully correct metabolic alterations related to hypothyroidism. We are not able to exclude that this feature may be influenced by the modulation of insulin sensitivity at the liver site, induced by LT4 oral administration.
Assuntos
Metabolismo Energético , Terapia de Reposição Hormonal/métodos , Hipotireoidismo/patologia , Obesidade/fisiopatologia , Descanso/fisiologia , Tiroxina/administração & dosagem , Adulto , Composição Corporal , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is not known whether the renal beneficial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa administration on the development of renal fibrosis in an experimental model of angiotensin II (Ang II)-dependent hypertension. METHODS: Sprague Dawley rats (n = 31) were divided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were euthanized and the kidneys were excised for histomorphometric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages) and types I and IV collagen expression. RESULTS: The administration of Ang II resulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal inflammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fibrosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). CONCLUSIONS: These data demonstrate that the treatment with Empa prevents the development of renal fibrosis in Ang II-dependent hypertension. In Ang II-dependent hypertension, the anti-fibrotic effect due to SGLT2 inhibition is caused by the reduction of inflammatory infiltrates and it is independent on the modulation of blood pressure increase.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Nefropatias/prevenção & controle , Rim/patologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Angiotensina II/fisiologia , Animais , Fibrose/etiologia , Fibrose/prevenção & controle , Hipertensão/complicações , Hipertensão/etiologia , Nefropatias/etiologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Fatty liver is believed to be sustained by a higher than normal adipose-derived NEFA flux to the liver. Also, hepatic energy metabolism may be a rate-limiting step of intrahepatic fat (IHF) accumulation. AIMS: To assess whole-body energy metabolism and hepatic high-energy phosphates (HEPs) in individuals with fatty liver. METHODS: We studied 22 individuals with fatty liver and 22 control individuals matched for anthropometric features by means of (1) hepatic 1H-magnetic resonance spectroscopy (MRS) to measure the IHF content, (2) hepatic 31P-MRS to assess the relative content of HEPs (phosphomonoesters, phosphodiesters, inorganic phosphorus, and ATP), and (3) indirect calorimetry to assess whole-body resting energy expenditure and substrate oxidation. RESULTS: Patients with newly diagnosed fatty liver and controls were not different for anthropometric parameters. Based on HOMA2%-S, individuals with fatty liver were more insulin resistant than controls. Resting energy expenditure and the pattern of substrate oxidation were not different between groups. Relative content of HEPs was not different between groups; in particular, the Pi/γ-ATP ratio, the most important signals in terms of monitoring energy homeostasis, was not different even if it was associated with indirect calorimetry-derived parameters of oxidative substrate disposal. CONCLUSIONS: These data demonstrate that fasting whole-body energy metabolism and the relative content of HEPs in nondiabetic patients with fatty liver are not different than those in controls when they are matched for anthropometric features.
Assuntos
Metabolismo Energético/fisiologia , Jejum/fisiologia , Fígado Gorduroso/terapia , Adulto , Estudos de Casos e Controles , Fígado Gorduroso/patologia , Feminino , Homeostase , Humanos , MasculinoRESUMO
AIMS: Compound 21 (C21), selective AT2 receptor agonist, has cardioprotective effects in experimental models of hypertension and myocardial infarction. The aims of the study was to evaluate the effect of C21, losartan, or both in Zucker diabetic fatty (ZDF) rats (type 2 diabetes) on (1) the prevention of myocardial hypertrophy; (2) myocardial expression of phosphatase and tensin homolog (PTEN), a target gene of miR-30a-3p, involved in myocardial remodelling. METHODS: Experiments were performed in ZDF (n = 33) and in control Lean (8) rats. From the 6th to the 20th week of age, we administered C21 (0.3 mg/kg/day) to 8 ZDF rats. 8 ZDF rats were treated with losartan (10 mg/kg/day), 8 rats underwent combination treatment, C21+ losartan, and 9 ZDF rats were left untreated. Blood glucose and blood pressure were measured every 4 weeks. At the end of the study the hearts were removed, the apex was cut for the quantification of PTEN mRNA and miR-30a-3p expression (realtime-PCR). Myocardial hypertrophy was evaluated by histomorphometric analysis, and nitrotyrosine expression (as marker of oxidative stress) by immunohistochemistry. RESULTS: ZDF rats had higher blood glucose (p < 0.0001) with respect to control Lean rats, while blood pressure did not change. Both parameters were not modified by C21 treatment, while losartan and losartan + C21 reduced blood pressure in ZDF rats (p < 0.05). miR-30a-3p expression was increased in ZDF rats (p < 0.01) and PTEN mRNA expression was decreased (p < 0.05). ZDF rats developed myocardial hypertrophy (p < 0.01) and increased oxidative stress (p < 0.01), both were prevented by C21 or losartan, or combination treatment. C21 or losartan normalized the expression of miR-30a-3p and PTEN. CONCLUSIONS: Activation of AT2 receptors or AT1 receptor blockade prevents the development of myocardial hypertrophy in ZDF rats. This occurs through the modulation of the miR-30a-3p/PTEN interaction.
Assuntos
Cardiomegalia/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Receptor Tipo 2 de Angiotensina/agonistas , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Cardiomegalia/etiologia , Cardiomegalia/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/patologia , Losartan/farmacologia , Masculino , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos ZuckerRESUMO
Compound 21 (C21), selective agonist of angiotensin type-2 (AT-2) receptors, shows anti-inflammatory effects in experimental models of hypertension and nephroprotection in diabetes. The aim of the present study was to evaluate the effects of C21 in cyclosporine nephropathy, which is characterized mainly by tubulo-interstitial fibrosis. Ten days before and during the experimental periods, low-salt diet was administered to Sprague-Dawley rats. Cyclosporine-A (CsA; 15 mg/kg per day, intraperitoneal injection) and CsA plus C21 (0.3 mg/kg per day, intraperitoneal injection) were administered for 1 and 4 weeks. Control groups were left without any treatment. Blood pressure (plethysmographic method) and 24 h urinary albumin excretion were measured once a week. At the end of the experimental protocols, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and type I and type IV collagen expression. After 1 and 4 weeks, the rats treated with CsA showed a significant increase (P<0.01) in blood pressure, no significant changes in urinary albumin excretion and a significant increase (P<0.01) in glomerular and tubulo-interstitial fibrosis and inflammatory infiltrates as compared with the control rats. Treatment with C21 did not modify the CsA dependent increase of blood pressure, which was higher than in control rats, but after 4 weeks of treatment significantly reduced (P<0.01) glomerular and tubulo-interstitial fibrosis, type 1 collagen expression and macrophage infiltration, as compared with rats treated with cyclosporine. The administration of C21 showed a protective effect on cyclosporine nephropathy, decreasing renal fibrosis and macrophage infiltration. These data suggest that C21 may counteract tubulo-interstitial fibrosis, the most potent predictor of the progression of renal diseases.
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The aim of this study was to evaluate the role of the angiotensin II (Ang II) induced-differential miRNA expression in renal glomerular and tubulo-interstitial fibrosis in an experimental model of Ang II-dependent hypertension. To clarify this issue, Sprague Dawley rats were treated with Ang II (200 ng/kg per minute, n = 15) or physiological saline (n = 14) for 4 weeks. Systolic blood pressure and albuminuria were measured every 2 weeks. At the end of the experimental period, renal glomerular and tubulo-interstitial fibrosis was evaluated by histomorphometric analysis, after Sirius-Red and Masson's trichrome staining. Ang II increased systolic blood pressure (P < 0.0001), albuminuria (P < 0.01) and both glomerular and tubulo-interstitial fibrosis (P < 0.01). Using laser capture microdissection and miRNA microarray analysis this study showed that miR-29a-3p was down-regulated in renal tubules and up-regulated in glomeruli. Real-time polymerase chain reaction (PCR) experiments confirmed in Ang II-treated rats a down-regulation of miR-29a-3p in tubules (P < 0.01), while no significant changes were observed in glomeruli. Matrix metalloproteinase-2 (MMP-2) was identified as putative miR-29a-3p target (by TargetScan, miRanda, Tarbase software) and functionally confirmed by luciferase activity assay. These data demonstrate that the effects of Ang II on miR-29a-3p expression in renal tubules is different from the one exerted in the glomeruli and that miR-29a-3p targets MMP-2. These results suggest that the development of renal fibrosis at glomerular and tubulo-interstitial level depends on different molecular mechanisms.
Assuntos
Angiotensina II/farmacologia , Hipertensão/genética , Hipertensão/patologia , Glomérulos Renais/patologia , Túbulos Renais/patologia , MicroRNAs/genética , Animais , Sequência de Bases , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fibrose , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/genética , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/fisiopatologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Masculino , Metaloproteinase 2 da Matriz/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
HIV infected subjects present an unfavorable cardiovascular (CV) risk profile that is determined by the infection itself, highly active anti-retroviral therapy (HAART) and other factors, such as chronic kidney disease (CKD). Information is scant and contradictory on whether these factors are associated with arterial stiffness and blood pressure (BP) alteration. Our study aimed to evaluate those parameters in HIV-positive subjects both with and without HAART and with and without CKD, which was defined as the presence of microalbuminuria with a normal glomerular filtration rate. We enrolled 94 HIV-infected subjects without known CV risk factors and compared them with 37 control subjects. We recorded brachial and central BP (pulse wave analysis) and pulse wave velocity ( SphygmoCor). HIV-positive subjects of similar ages and with similar BP values showed central pulse pressure values that were significantly greater than those of controls; this was also the case for the Aix value. Central systolic and pulse pressure values and Aix were significantly greater in HIV-positive subjects with HAART and CKD than in the other HIV-positive subgroups and control subjects. PWV was also superimposable between groups when the data were analyzed relative to the presence of HAART and CKD. Our study shows that the unfavorable CV risk profile associated with HIV infection includes an increase in both central BP and Aix. The central BP increase seems to be favored by renal damage, which apparently has a role in the early stages of the disease.
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Velocidade do Fluxo Sanguíneo/fisiologia , Pressão Sanguínea/fisiologia , Infecções por HIV/fisiopatologia , Falência Renal Crônica/fisiopatologia , Adulto , Determinação da Pressão Arterial , Feminino , Taxa de Filtração Glomerular/fisiologia , Infecções por HIV/complicações , Humanos , Rim/fisiopatologia , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Fluxo Pulsátil/fisiologiaRESUMO
The aim of this study was to evaluate the effect of compound 21 (C21), a selective AT2 receptor agonist, on diabetic nephropathy and the potential additive effect of C21, when associated with losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The experiments lasted 15 wk (from 5 to 20 wk of age) and were performed in 40 ZDF rats and 12 control lean rats. ZDF rats were divided into 4 groups: 1) 9 rats were treated with losartan; 2) 10 rats were treated with C21; 3) 9 rats were treated with losartan plus C21; and 4) 12 rats were maintained without any treatment. ZDF rats showed an increase in blood glucose level, albuminuria, renal fibrosis, macrophage infiltration, and TNF-α expression and a reduction of glomerular nephrin expression compared with control lean rats. C21 treatment reduced renal glomerular, tubulointerstitial, and perivascular fibrosis, and macrophage infiltration and TNF-α expression in ZDF rats. C21 treatment caused a decrease in albuminuria in ZDF rats up to 11 wk of age. Losartan decreased macrophage infiltration, TNF-α expression, and renal glomerular and perivascular fibrosis, restored glomerular nephrin expression, but did not affect tubulointerstitial fibrosis. Losartan treatment caused a decrease in albuminuria in ZDF rats up to 15 wk of age. At the end of the protocol, only the combination of C21 plus losartan significantly reduced albuminuria in ZDF rats. These data demonstrate that C21 has beneficial effects on diabetic nephropathy, suggesting the combination of C21 and losartan as a novel pharmacological tool to slow the progression of nephropathy in type II diabetes.
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Nefropatias Diabéticas/prevenção & controle , Receptor Tipo 2 de Angiotensina/agonistas , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Albuminúria/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/urina , Avaliação Pré-Clínica de Medicamentos , Fibrose , Interleucina-10/metabolismo , Rim/metabolismo , Rim/patologia , Losartan , Masculino , Proteínas de Membrana/metabolismo , Ratos Zucker , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Micro-RNAs (miRNAs) are a class of small non-coding RNAs, recently emerged as a post-transcriptional regulator having a key role in various cardiac pathologies. Among them, cardiac fibrosis that occurs as a result from an imbalance of extracellular matrix proteins turnover and is a highly debilitating process that eventually lead to organ dysfunction. An emerging theme on is that miRNAs participate in feedback loop with transcription factors that regulate their transcription. NF-κB, a key transcription factor regulator controls a series of gene program in various cardiac diseases through positive and negative feedback mechanism. But, NF-κB mediated miRNA regulation in cardiac fibrosis remains obscure. Bioinformatics analysis revealed that miR-26a has targets collagen I and CTGF and possesses putative NF-κB binding element in its promoter region. Here, we show that inhibition of NF-κB in cardiac fibroblast restores miR-26a expression, attenuating collagen I, and CTGF gene expression in the presence of Ang II, conferring a feedback regulatory mechanism in cardiac fibrosis. The target genes for miR-26a were confirmed using 3'-UTR luciferase reporter assays for collagen I and CTGF genes. Using NF-κB reporter assays, we determine that miR-26a overexpression inhibits NF-κB activity. Finally, we show that miR-26a expression is restored along with the attenuation of collagen I and CTGF genes in cardiac specific IkBa triple mutant transgenic mice (preventing NF-κB activation) subjected to 4 weeks transverse aortic banding (TAC), compared to wild type (WT) mice. The data indicate a potential role of miR-26a in cardiac fibrosis and, offer novel therapeutic intervention.
Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Angiotensina II/farmacologia , Animais , Células Cultivadas , Colágeno Tipo I/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Modelos Cardiovasculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologiaRESUMO
OBJECTIVES: A direct measurement of carotid stiffness implies an accurate assessment of changes in carotid diameter and pressure during cardiac cycle. Radiofrequency-based wall-tracking systems (WTS) are capable to track arterial wall movement with adequate spatial and temporal resolution, and to provide carotid pressure estimate from calibrated distension waveforms. The aim of the present study was to compare the values of carotid distension and beta-stiffness index acquired in the same population by two commercially available WTS, in order to determine whether their measures can be pooled in clinical studies. In addition, a local carotid pulse pressure (PP) obtained from calibrated distension waveforms was compared with that obtained from pressure waveforms. METHODS: In 105 patients, right common carotid artery (CCA) systo-diastolic excursions were assessed during the same session and by the same operator both by WTS implemented in Esaote system (QAS, MyLab) and in Aloka system (E-track; Alpha 10). In 78 patients, carotid PP was also estimated by applanation tonometry. RESULTS: Despite comparable blood pressure and heart rate values during the two acquisitions, CCA distension was significantly lower (363 ± 162 vs. 458 ± 176 µm, P < 0.0001) and beta-stiffness index (11.9 ± 5.5 vs. 9.4 ± 3.8, P < 0.0001) higher with Esaote as compared to Aloka. PP obtained from calibrated pressure and distension waveforms was comparable (42.6 ± 11.4 vs. 43.0 ± 10.7 mmHg, P = 0.51). CONCLUSIONS: The values of carotid distension and stiffness obtained by two different WTS are not interchangeable and cannot be merged into a common database. Calibrated distension curves may provide an acceptable estimate of local carotid pressure.
Assuntos
Artérias Carótidas/fisiopatologia , Técnicas de Imagem por Elasticidade/métodos , Hipertensão/fisiopatologia , Resistência Vascular/fisiologia , Adulto , Artérias Carótidas/diagnóstico por imagem , Elasticidade , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Rigidez Vascular/fisiologiaRESUMO
MicroRNAs play an important role in myocardial diseases. MiR-133a regulates cardiac hypertrophy, while miR-29b is involved in cardiac fibrosis. The aim of this study was to evaluate whether miR-133a and miR-29b play a role in myocardial fibrosis caused by Angiotensin II (Ang II)-dependent hypertension. Sprague-Dawley rats were treated for 4 weeks with Ang II (200 ng/kg/min) or Ang II + irbesartan (50 mg/kg/day in drinking water), or saline by osmotic minipumps. At the end of the experimental period, cardiac miR-133a and miR-29b expression was measured by real-time PCR, and myocardial fibrosis was evaluated by morphometric analysis. A computer-based prediction algorithm led to the identification of collagen 1a1 (Col1A1) as a putative target of miR-133a. A reporter plasmid bearing the 3'-untranslated regions (UTRs) of Col1A1 mRNA was constructed and luciferase assay was performed. MiR-133a suppressed the activity of luciferase when the reporter gene was linked to a 3'-UTR segment of Col1A1 (P < 0.01). Mutation of miR-133a binding sites in the 3'-UTR of Col1A1 mRNA abolished miR-133a-mediated repression of reporter gene activity, showing that Col1A1 is a real target of miR-133a. In vivo, Ang II caused an increase in systolic blood pressure (P < 0.0001, tail cuff) and myocardial fibrosis in presence of a decrease in miR-133a (P < 0.01) and miR-29b (P < 0.01), and an increase in Col1A1 expression (P < 0.01). These effects were abolished by Ang II administration + irbesartan. These data demonstrate a relationship between miR-133a and Col1A1, suggesting that myocardial fibrosis occurring in Ang II-dependent hypertension is regulated by the down-regulation of miR-133a and miR-29b through the modulation of Col1A1 expression.
Assuntos
Angiotensina II/metabolismo , Colágeno Tipo I/metabolismo , Fibrose/metabolismo , Cardiopatias/metabolismo , Hipertensão/metabolismo , MicroRNAs/metabolismo , Angiotensina II/genética , Animais , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Regulação da Expressão Gênica/fisiologia , Masculino , MicroRNAs/genética , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To evaluate oxidative stress in uremia and dialysis and chromogranin A, a stress hormone that could be related to oxidative processes. METHODS: Plasma oxidative stress biomarkers (-SH, 8-OHdG, and ox-LDL) and chromogranin A were measured in 89 outpatients (21 uremic patients, 17 in peritoneal dialysis, and 51 in haemodialysis), and in 18 subjects with normal renal function. RESULTS: -SH groups were significantly reduced in heamodialysis, peritoneal, and uremic patients as compared with the control group (p=0.01), while 8-OHdG was increased (p<0.01). No differences were observed for ox-LDL. Chromogranin A was increased in uremic, peritoneal and haemodialysis patients (p<0.01), showing a positive correlation to 8-OHdG (p<0.01). CONCLUSION: Oxidative stress biomarkers and chromogranin A levels differ between control subjects when compared to both uremic and dialysis patients. No differences were observed between uremic and dialysis patients, suggesting that uremia is the major source of the increase in oxidative stress and CgA levels in patients with end stage renal disease.