RESUMEN
Hypertension-induced renal fibrosis contributes to the progression of chronic kidney disease, and apigenin, an anti-hypertensive flavone that is abundant in celery, acts as an agonist of transient receptor potential vanilloid 4 (TRPV4). However, whether apigenin reduces hypertension-induced renal fibrosis, as well as the underlying mechanism, remains elusive. In the present study, the deoxycorticosterone acetate (DOCA)-salt hypertension model was established in male Sprague-Dawley rats that were treated with apigenin or vehicle for 4 weeks. Apigenin significantly attenuated the DOCA-salt-induced structural and functional damage to the kidney, which was accompanied by reduced expression of transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signaling pathway and extracellular matrix proteins. Immunochemistry, cell-attached patch clamp and fluorescent Ca2+ imaging results indicated that TRPV4 was expressed and activated by apigenin in both the kidney and renal cells. Importantly, knockout of TRPV4 in mice abolished the beneficial effects of apigenin that were observed in the DOCA-salt hypertensive rats. Additionally, apigenin directly inhibited activation of the TGF-ß1/Smad2/3 signaling pathway in different renal tissues through activation of TRPV4 regardless of the type of pro-fibrotic stimulus. Moreover, the TRPV4-mediated intracellular Ca2+ influx activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway, which inhibited the TGF-ß1/Smad2/3 signaling pathway. In summary, dietary apigenin has beneficial effects on hypertension-induced renal fibrosis through the TRPV4-mediated activation of AMPK/SIRT1 and inhibition of the TGF-ß1/Smad2/3 signaling pathway. This work suggests that dietary apigenin may represent a promising lifestyle modification for the prevention of hypertension-induced renal damage in populations that consume a high-sodium diet.
Asunto(s)
Apigenina/uso terapéutico , Suplementos Dietéticos , Hipertensión Renal/dietoterapia , Riñón/patología , Canales Catiónicos TRPV/fisiología , Proteínas Quinasas Activadas por AMP/fisiología , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Apigenina/farmacología , Presión Sanguínea/efectos de los fármacos , Calcio/metabolismo , Acetato de Desoxicorticosterona , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Fibrosis , Hipertensión Renal/inducido químicamente , Hipertensión Renal/metabolismo , Hipertensión Renal/fisiopatología , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Ratas Sprague-Dawley , Sirtuina 1/fisiología , Cloruro de Sodio Dietético , Canales Catiónicos TRPV/metabolismoRESUMEN
The mechanisms underlying the anti-inflammatory and antihypertensive effects of long-chain ω-3 polyunsaturated fatty acids (ω-3 PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid epoxyeicosatrienoic acids also exhibit antihypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may lower the blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for 3 weeks in a murine model of angiotensin-II-dependent hypertension. Also, because EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of an sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II, increased the blood pressure, further increased the renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (ie, prostaglandins and MCP-1), downregulated an epithelial sodium channel, and upregulated angiotensin-converting enzyme-2 message and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering systolic blood pressure and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by upregulation of angiotensin-converting enzyme-2 in angiotensin-II-dependent hypertension.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antihipertensivos/uso terapéutico , Suplementos Dietéticos , Modelos Animales de Enfermedad , Epóxido Hidrolasas/antagonistas & inhibidores , Ácidos Grasos Omega-3/uso terapéutico , Hipertensión Renal/dietoterapia , Angiotensina II , Enzima Convertidora de Angiotensina 2 , Animales , Antiinflamatorios no Esteroideos/metabolismo , Antihipertensivos/metabolismo , Terapia Combinada , Inhibidores Enzimáticos/uso terapéutico , Bloqueadores del Canal de Sodio Epitelial/metabolismo , Bloqueadores del Canal de Sodio Epitelial/uso terapéutico , Canales Epiteliales de Sodio/química , Canales Epiteliales de Sodio/metabolismo , Epóxido Hidrolasas/química , Epóxido Hidrolasas/metabolismo , Ácidos Grasos Omega-3/metabolismo , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/inmunología , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Peptidil-Dipeptidasa A/biosíntesis , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Distribución Aleatoria , SolubilidadRESUMEN
Blood pressure naturally rises with increasing age. The rate of change in blood pressure with age is regulated in part by genetic factors, but can also be altered through sustained dietary modification. Dietary approaches to modify blood pressure remain an important part of cardiovascular health promotion, which is especially important given the aging of the general population coupled with the increasing prevalence of obesity and metabolic disturbances. Specific modification of dietary components such as macronutrients and micronutrients could be helpful to lower blood pressure and alter the slope of blood pressure change whereas nutritional supplements are less likely to have a substantial beneficial effect. Population-wide generalizations regarding diet are impractical as individualized strategies are more likely to be successful in facilitating long-term benefits in improving blood-pressure control. Consequently, more effort needs to be focused on evaluating data from large-scale observational and interventional studies and interpreting their information in a clinically relevant manner, which is likely to be helpful for individual patients. Providing education on the relationship between diet and blood pressure from an early age is most likely to produce tangible benefits.
Asunto(s)
Hipertensión Renal/dietoterapia , Hipertensión Renal/prevención & control , Enfermedades Metabólicas/dietoterapia , Obesidad/dietoterapia , Humanos , Hipertensión Renal/epidemiología , Enfermedades Metabólicas/epidemiología , Obesidad/epidemiología , PrevalenciaRESUMEN
AIMS: Reduced bioavailability of endogenous nitric oxide (NO) is a central pathophysiological event in hypertension and other cardiovascular diseases. Recently, it was demonstrated that inorganic nitrate from dietary sources is converted in vivo to form nitrite, NO, and other bioactive nitrogen oxides. We tested the hypothesis that dietary inorganic nitrate supplementation may have therapeutic effects in a model of renal and cardiovascular disease. METHODS AND RESULTS: Sprague-Dawley rats subjected to unilateral nephrectomy and chronic high-salt diet from 3 weeks of age developed hypertension, cardiac hypertrophy and fibrosis, proteinuria, and histological as well as biochemical signs of renal damage and oxidative stress. Simultaneous nitrate treatment (0.1 or 1 mmol nitrate kg⻹ day⻹), with the lower dose resembling the nitrate content of a diet rich in vegetables, attenuated hypertension dose-dependently with no signs of tolerance. Nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated. Mechanistically, dietary nitrate restored the tissue levels of bioactive nitrogen oxides and reduced the levels of oxidative stress markers in plasma (malondialdehyde) and urine (Class VI F2-isoprostanes and 8-hydroxy-2-deoxyguanosine). In addition, the increased circulating and urinary levels of dimethylarginines (ADMA and SDMA) in the hypertensive rats were normalized by nitrate supplementation. CONCLUSION: Dietary inorganic nitrate is strongly protective in this model of renal and cardiovascular disease. Future studies will reveal if nitrate contributes to the well-known cardioprotective effects of a diet rich in vegetables.
Asunto(s)
Presión Sanguínea/fisiología , Hipertensión Renal/dietoterapia , Hipertensión Renal/metabolismo , Nitratos/metabolismo , Estrés Oxidativo/fisiología , Animales , Arginina/análogos & derivados , Arginina/metabolismo , Cardiomegalia/dietoterapia , Cardiomegalia/metabolismo , Cardiomegalia/prevención & control , Modelos Animales de Enfermedad , Hipertensión Renal/prevención & control , Riñón/metabolismo , Masculino , Nefrectomía , Óxido Nítrico/metabolismo , Nitrógeno/metabolismo , Proteinuria/dietoterapia , Proteinuria/metabolismo , Proteinuria/prevención & control , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio Dietético/metabolismo , Cloruro de Sodio Dietético/farmacologíaRESUMEN
BACKGROUND: Spontaneously hypertensive rats (SHR) are born normotensive and develop hypertension (HTN) later in life (age 4 to 5 weeks). HTN in SHR is associated with and caused in part, by oxidative stress and renal interstitial inflammation. This study tested the hypothesis that lifelong antioxidant supplementation beginning at prenatal period may delay the onset and reduce the severity of HTN in SHR. The study further sought to explore the effect of diet modification on renal tissue NAD(P)H oxidase and calcineurin abundance. METHODS: Pregnant SHR and their offspring were fed either an antioxidant-fortified diet (a chow containing alpha-tocopherol 5000 IU/kg, ascorbic acid 500 ppm, selenium 2.76 ppm, and zinc 350 ppm) or regular diet (alpha-tocopherol 40 IU/kg, selenium 0.2 ppm, and zinc 70 ppm). Animals were observed for 24 weeks. Wistar-Kyoto rats fed either a regular or antioxidant diet served as control. RESULTS: Onset of HTN was delayed and severity of HTN was reduced in antioxidant-treated compared with untreated SHR. Markers of oxidative stress (i.e., plasma hydrogen peroxide, renal tissue malondialdehyde, and nitrotyrosine abundance) were elevated in untreated but not in antioxidant-treated SHR. gp91phox and p22phox subunits of NAD(P)H oxidase were markedly elevated in the renal cortex of untreated SHR and partially restored in the treated SHR. Similarly, renal calcineurin Aalpha and B subunits were elevated in untreated SHR and were partially restored in the treated SHR. Antioxidant therapy had no effect on the measured parameters in the WKY control. CONCLUSION: Lifelong consumption of antioxidant-rich diet ameliorates HTN and oxidative stress in SHR. This is associated with the reduction of superoxide-generating enzyme, NAD(P)H oxidase, and immunoregulatory factor calcineurin. Antioxidant-rich diet appears to attenuate oxidative stress, not only by fortifying antioxidant defense capacity but also by lowering NAD(P)H oxidase, which is a major source of reactive oxygen species.
Asunto(s)
Antioxidantes/farmacología , Calcineurina/metabolismo , Hipertensión Renal/dietoterapia , Hipertensión Renal/metabolismo , NADPH Oxidasas/metabolismo , Alimentación Animal , Animales , Ácido Ascórbico/farmacología , Presión Sanguínea , Femenino , Alimentos Fortificados , Riñón/metabolismo , Estrés Oxidativo , Embarazo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Selenio/farmacología , Regulación hacia Arriba , alfa-Tocoferol/farmacologíaRESUMEN
Three dietary measures are useful for chronic progressive renal failure. In a hypertensive patient, salt restriction is a prerequisite for antihypertensive therapy. Protein restriction to 0.6 g/kg of body weight per day can slow down progression of renal disease with the exception of polycystic disease of the adult type. Ketosteril can be given for prevention of essential amino acid deficiency. A normalization of serum phosphorus is essential for slowing progression of disease as well as bone metabolism. Therefore, a diet reduced in phosphates, supported by phosphate binders is prescribed.