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/metabolismoAsunto(s)
Carcinógenos/efectos adversos , Medicina de Hierbas , Hipertensión Renal/terapia , Fallo Renal Crónico/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Animales , Pueblo Asiatico , Humanos , Hipertensión Renal/inducido químicamente , Fallo Renal Crónico/inducido químicamente , Neoplasias Renales/inducido químicamenteRESUMEN
OBJECTIVES: We evaluated whether taurine prevents renal damage which is accompanied with enhanced expression of lectin-like oxidized low-density lipoprotein (OxLDL) receptor-1 (LOX-1) mRNA, in salt-loaded Dahl salt-sensitive (DS) rats. METHODS: Male, 4-week-old DS rats were fed on either a high-salt (8% NaCl) or normal-salt (0.66% NaCl) diet for 4 weeks. Some DS rats with high-salt diet were given drinking water containing 1% taurine. We evaluated blood pressure, renal function, renal LOX-1 expression and parameters for oxidative stress. RESULTS: In salt-loaded DS rats, there was a significant increase in heart weight and urinary protein, accompanied with enhanced LOX-1 expression in kidney. All of these were reduced by concomitant supplementation of taurine, although both antihypertensive and antihyperlipidemic effects of taurine were only slight in salt-loaded DS rats. On the other hand, salt-induced increment in urinary 8-hydroxy-deoxyguanosine, a parameter of oxidative damage, was completely normalized by taurine supplementation. CONCLUSIONS: The protective effects of taurine supplementation against renal damage induced by salt loading in DS rats may be attributed to the suppression of LOX-1, probably through its antioxidant effects.
Asunto(s)
Guanosina/análogos & derivados , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/metabolismo , Taurina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Guanosina/orina , Hipertensión Renal/inducido químicamente , Lipoproteínas LDL/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Proteinuria/inducido químicamente , Proteinuria/tratamiento farmacológico , Proteinuria/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Endogámicas Dahl , Receptores de LDL/genética , Receptores de LDL/metabolismo , Cloruro de Sodio DietéticoAsunto(s)
Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Donantes de Sangre , Transfusión de Sangre Autóloga , Relación Dosis-Respuesta a Droga , Epoetina alfa , Eritropoyetina/efectos adversos , Honorarios Farmacéuticos , Infecciones por VIH/tratamiento farmacológico , Hipertensión Renal/inducido químicamente , Neoplasias/tratamiento farmacológico , Premedicación , Cuidados Preoperatorios/métodos , Proteínas Recombinantes , Insuficiencia Renal/tratamiento farmacológicoRESUMEN
BACKGROUND: Cyclosporine A (CsA)-induced hypertension and nephrotoxicity are aggravated by high sodium intake. Accumulating evidence suggests that potassium and magnesium supplementation could protect against the detrimental effects of dietary salt. In the present study, we tested the hypothesis of whether concurrent supplementation with potassium and magnesium could protect against the development of CsA-induced hypertension and nephrotoxicity more effectively than supplementation with one mineral alone. METHODS: Eight-week-old spontaneously hypertensive rats (SHRs) were divided into four groups (N = 10 in each group): (1) CsA group (5 mg/kg subcutaneously) receiving high-sodium diet (Na 2.6%, K 0.8%, Mg 0.2% wt/wt); (2) CsA group receiving a high-sodium, high-potassium diet (Na 2.6%, K 2.4%, Mg 0.2%); (3) CsA group receiving high-sodium, high-magnesium diet (Na 2.6%, K 0.8%, Mg 0.6%); and (4) CsA group receiving high-sodium, high-potassium, high-magnesium diet (Na 2.6%, K 2.4%, Mg 0.6%). RESULTS: CsA induced severe hypertension and deteriorated renal functions in SHRs on high-sodium diet. Histologically, the kidneys showed severe thickening of the media of the afferent artery with fibrinoid necrosis. Potassium supplementation lowered blood pressure (198 +/- 5 vs. 212 +/- 2 mm Hg, P < 0.05) and partially prevented the development of proteinuria (-25%, P < 0.05). Magnesium supplementation decreased blood pressure to the same extent but improved renal functions more effectively than potassium. The greatest protection against CsA toxicity was achieved when dietary potassium and magnesium supplementations were combined. Urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion, a marker for renal proximal tubular damage, increased progressively in CsA-treated SHRs on the high-sodium diet. Neither potassium nor magnesium influenced urinary NAG excretion. We also estimated the activity of the renal dopaminergic system by measuring 24-hour urinary dopamine excretion rates. CsA suppressed the renal dopaminergic system during high-sodium diet. Magnesium supplementation, alone and in combination with potassium, protected against the development of renal dopaminergic deficiency in CsA-treated SHRs on high-sodium diet. Magnesium supplementation increased plasma-free ionized magnesium (iMg) and bone magnesium by 50 and 16%, respectively. CONCLUSIONS: Our findings indicate that both potassium and magnesium supplementations showed beneficial effects against CsA-induced hypertension and nephrotoxicity. The protective effect of magnesium clearly exceeded that of potassium. The greatest protection against CsA toxicity was achieved when potassium and magnesium were combined. We also provide evidence that the development of CsA-induced glomerular, tubular, and vascular lesions are associated with renal dopaminergic deficiency.
Asunto(s)
Ciclosporina/toxicidad , Hipertensión Renal/inducido químicamente , Hipertensión Renal/tratamiento farmacológico , Inmunosupresores/toxicidad , Magnesio/farmacología , Potasio en la Dieta/farmacología , Acetilglucosaminidasa/orina , Animales , Presión Sanguínea , Huesos/química , Colesterol/sangre , Ciclosporina/sangre , Ciclosporina/farmacocinética , Dopamina/fisiología , Frecuencia Cardíaca , Hipertensión Renal/patología , Hipertrofia Ventricular Izquierda/inducido químicamente , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/patología , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , Fallo Renal Crónico/inducido químicamente , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/patología , Túbulos Renales Proximales/química , Túbulos Renales Proximales/patología , Magnesio/análisis , Masculino , Miocardio/química , Norepinefrina/orina , Proteinuria/inducido químicamente , Proteinuria/tratamiento farmacológico , Proteinuria/patología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sodio en la Dieta/farmacología , Distribución TisularRESUMEN
BACKGROUND: We have recently found evidence for increased reactive oxygen species (ROS) in rats with lead-induced hypertension. We hypothesized that increased ROS activity may contribute to hypertension by enhancing inactivation of nitric oxide (NO) in this model. METHODS: Rats were treated for 12 weeks with either lead acetate (100 p.p.m.) alone (Pb group) or lead acetate plus vitamin E-fortified food (5000 U/kg rat chow, Pb + E group). The control animals were fed either regular rat chow or a vitamin E-fortified diet. Blood pressure, creatinine clearance, and urinary excretion of stable NO metabolites (NOx) were monitored, and plasma and tissue abundance of nitrotyrosine, which is the footprint of NO oxidation by ROS, were determined. RESULTS: The Pb group showed a marked rise in blood pressure, a significant increase in plasma and kidney, heart, liver, and brain nitrotyrosine abundance, and a substantial fall in urinary NOx excretion. Concomitant administration of high-dose vitamin E in the Pb + E group ameliorated hypertension and normalized both urinary NOx excretion and tissue nitrotyrosine without altering tissue lead content. However, vitamin E supplementation had no discernible effect on either blood pressure or nitrotyrosine abundance in the normal controls. CONCLUSIONS: These findings point to enhanced ROS-mediated inactivation and sequestration of NO, which can potentially contribute to hypertension, tissue damage, and reduced urinary NOx excretion in rats with lead-induced hypertension. The beneficial effects of high-dose vitamin E on blood pressure, tissue nitrotyrosine burden, and urinary NOx excretion support the role of increased ROS activity in the pathogenesis of these abnormalities in this model.
Asunto(s)
Hipertensión Renal/inducido químicamente , Hipertensión Renal/metabolismo , Intoxicación por Plomo/metabolismo , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/farmacología , Presión Sanguínea , Western Blotting , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Riñón/química , Riñón/efectos de los fármacos , Riñón/metabolismo , Plomo/toxicidad , Intoxicación por Plomo/complicaciones , Hígado/química , Hígado/metabolismo , Masculino , Miocardio/química , Miocardio/metabolismo , Dióxido de Nitrógeno/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , Tirosina/análogos & derivados , Tirosina/análisis , Tirosina/sangre , Vitamina E/farmacologíaRESUMEN
Genetic factors are important in determining the susceptibility to renal damage. In a backcross of the hypertensive and proteinuric fawn-hooded Erasmus University Rotterdam (FHH/EUR) rat with the normotensive, nonproteinuric August Copenhagen Irish (ACI/EUR) rat, two genes (denoted Rf-1 and Rf-2) were genetically mapped for parameters of functional and structural renal damage. The aim of the present study was to investigate the susceptibility to functional and structural renal damage in heterozygous (FHH X ACI) F1 rats compared with the parental FHH and ACI strains at similar levels of systolic BP (SBP). BP elevation was induced by chronic treatment with NG-nitro-L-arginine methyl ester (L-NAME) in either a low dose (LD, 75 to 100 mg/L) or a high dose (HD, 175 to 250 mg/L) in the drinking fluid. Survival of FHH rats and, to a lesser extent, F1 rats, was adversely affected by L-NAME treatment. All ACI rats except for one ACI-HD animal survived. In all strains, L-NAME caused a dose-dependent increase in SBP. At similar levels of SBP, the increase in functional renal damage, as indicated by the level of albuminuria, was higher in F1 compared with ACI, but lower compared with FHH. The same differences were found for the level of structural renal damage, as indicated by the incidence of glomerulosclerosis. Both the SBP and the average BP burden (SBP-Av), defined as SBP averaged over the period of follow-up, directly correlated with the level of albuminuria and incidence of glomerulosclerosis in all strains. However, the increase in the degree of renal damage per mmHg increase in SBP or SBP-Av was significantly higher in the F1 rats compared with ACI, but lower compared with FHH rats. Values for these F1 rats were closer to the ACI rats than to values for the FHH rats and increased above an SBP level of 180 mmHg. The F1 rats, being heterozygous for Rf-1 and Rf-2, as well as for other potential genes responsible for renal disease, were largely, but not completely, protected from hypertension-induced renal damage. It is concluded that complete susceptibility to hypertension-associated renal damage in rats primarily depends on the presence of predisposing genes for renal failure even after a significant increase in BP.
Asunto(s)
Hipertensión Renal/complicaciones , Insuficiencia Renal/etiología , Animales , Autopsia , Presión Sanguínea/fisiología , Peso Corporal/fisiología , Creatinina/metabolismo , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Humanos , Hipertensión Renal/inducido químicamente , Hipertensión Renal/fisiopatología , Incidencia , Lactante , NG-Nitroarginina Metil Éster/efectos adversos , Ratas , Ratas Endogámicas , Análisis de Regresión , Insuficiencia Renal/genética , Insuficiencia Renal/fisiopatología , Índice de Severidad de la Enfermedad , Especificidad de la Especie , Sobrevida , SístoleRESUMEN
A diet fortified with calcium carbonate has been reported to reduce blood pressure in low-renin and salt-sensitive hypertensive patients. We have therefore examined the effect of increased dietary calcium on the development of reduced renal mass-saline hypertension in rats, a classical, low-renin, volume, and sodium-dependent model of hypertension. Rats with 70-75% reduction in renal mass were divided into experimental and control groups. The experimental rats were fed a sodium-free diet supplemented with calcium carbonate (2.0% calcium) and drank 1% saline for 5 weeks. Control rats consumed the salt-free diet and drank 1% saline for the same period. In control rats, as previously observed, blood pressure progressive increased from a control value of 120.0 +/- 1.2 to 174.2 +/- 1.2 mm Hg by the fifth week. In contrast, in the calcium-supplemented rats the development of hypertension was significantly attenuated; the blood pressure only increased from 117.0 +/- 1.2 to 134.0 +/- 3.8 mm Hg by the fifth week. This was associated with a 30% decrease in saline intake by the fifth week, with proportionate decreases in urine volume and sodium excretion but not potassium excretion. Urinary magnesium excretion increased. No such changes were seen in control rats. At the end of the treatment period, plasma levels of sodium, potassium, calcium, creatinine, BUN, and protein were not different, but plasma chloride and magnesium were lower in experimental rats; vascular smooth muscle cell membrane potentials were also not different. These data show that dietary calcium carbonate can attenuate the development of reduced renal mass-saline hypertension in the rat, possibly in part by altering sodium and water intake.