RESUMEN
Increased body weight (BW) induces inappropriate renin-angiotensin system (RAS) activation. The activation of the intrarenal RAS is associated with increased urinary angiotensinogen (uAGT), blood pressure (BP), and kidney damage. Here, we examined uAGT excretion levels in young non-diabetic human subjects with overweight (OW) and non-diabetic mice with high-fat diet (HFD)-induced OW. Human subjects (women and men; 20-28 years old) included two groups: (a) overweight (OW, n = 17, BMI ≥ 25); and (b) controls (normal weight (NW; n = 26, BMI ≤ 25). In these subjects, we measured BP, albuminuria, and protein levels of uAGT by ELISA adjusted by urinary creatinine (expressed by uAGT/uCrea). Mice (female and male C57BL/6J mice, 8 ± 2 weeks of age) also included two groups: HFD or normal fat diet (NFD) fed for 8 weeks. We measured BW, fasting blood glucose (FBG), BP by telemetry, albuminuria, and uAGT by ELISA. In humans: (i) no significant changes were observed in BP, albuminuria, and FBG when comparing NW and OW subjects; (ii) multivariate logistic regression analysis of independent predictors related to uAGT/uCrea levels demonstrated a strong association between uAGT and overweight; (iii) urinary reactive oxygen species (ROS) were augmented in men and women with OW; (iv) the uAGT/uCrea ratio was higher in men with OW. However, the uAGT/uCrea values were lower in women even with OW. In mice: (i) males fed an HFD for 8 weeks became OW while females did not; (ii) no changes were observed either in FBG, BP, or albuminuria; (iii) kidney ROS were augmented in OW male mice after 28 weeks but not in females; (iv) OW male mice showed augmented excretion of uAGT but this was undetectable in females fed either NFD or HFD. In humans and mice who are OW, the urinary excretion of AGT differs between males and females and overcomes overt albuminuria.
Asunto(s)
Angiotensinógeno , Sobrepeso , Sistema Renina-Angiotensina , Caracteres Sexuales , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Adulto Joven , Albuminuria , Angiotensinógeno/orina , Ratones Endogámicos C57BL , Especies Reactivas de OxígenoRESUMEN
Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hipertensión , ATPasas de Translocación de Protón Vacuolares , Femenino , Masculino , Ratones , Animales , Renina , Receptor de Prorenina , Dieta Alta en Grasa/efectos adversos , Especies Reactivas de Oxígeno , Ratones Endogámicos C57BL , Sistema Renina-Angiotensina/genética , Receptores de Superficie Celular/genética , Presión SanguíneaRESUMEN
Prolonged high-fat diet (HFD) accelerates the cardiovascular, renal, and metabolic dysfunction in hypertensive rats with altered renal development (ARDev). Soluble guanylate cyclase (sGC) stimulation or sodium-glucose cotransporter 2 (SGLT2) inhibition may improve cardiovascular, renal, and metabolic function in settings of hypertension and obesity. This study examined whether 6 wk treatment with an SGLT2 inhibitor (empagliflozin, 7 mg/kg/day) enhances the cardiovascular, renal, and metabolic effects of a sGC stimulator (praliciguat, 10 mg/kg/day) in hypertensive rats with ARDev and prolonged exposure to HFD. Arterial pressure (AP), renal vascular resistance (RVR), fat abdominal volume (FAV), insulin resistance, leptin and triglycerides levels, and intrarenal infiltration of inflammatory cells were higher, but cardiac output and creatinine clearance were lower in hypertensive rats (n = 15) than in normotensive rats (n = 7). Praliciguat administration (n = 10) to hypertensive rats reduced (P < 0.05) AP, FAV, plasma concentrations of leptin and triglycerides, and increased (P < 0.05) cardiac output and creatinine clearance. Empagliflozin administration (n = 8) only increased (P < 0.05) glucosuria and creatinine clearance and decreased (P < 0.05) plasma leptin and triglycerides concentrations in hypertensive rats. Simultaneous administration of praliciguat and empagliflozin (n = 10) accelerated the decrease in AP, improved glucose tolerance, reduced (P < 0.05) incremental body weight gain, and decreased (P < 0.05) insulin resistance index, RVR, and the infiltration of T-CD3 lymphocytes in renal cortex and renal medulla. In summary, the combined administration of praliciguat and empagliflozin leads to a greater improvement of the cardiovascular, renal, and metabolic dysfunction secondary to prolonged exposure to HFD in hypertensive rats with ARDev than the treatment with either praliciguat or empagliflozin alone.NEW & NOTEWORTHY This is the first study, to our knowledge, showing that SGLT2 inhibition potentiates the beneficial cardiovascular, renal, and metabolic effects elicited by sGC stimulation in hypertensive rats with prolonged high-fat diet. The effects of the simultaneous administration of praliciguat and empagliflozin are greater than those elicited by either one alone. The effects of the simultaneous treatment may be related to a greater reduction in the inflammatory status.
Asunto(s)
Hipertensión , Resistencia a la Insulina , Animales , Compuestos de Bencidrilo/farmacología , Creatinina , Dieta Alta en Grasa/efectos adversos , Glucosa , Leptina , Ratas , Transportador 2 de Sodio-Glucosa , Guanilil Ciclasa Soluble , TriglicéridosRESUMEN
The mechanisms involved in renal dysfunction induced by high-fat diet (HFD) in subjects with altered renal development (ARDev) are understudied. The objective of this study is to examine whether there are sex-dependent differences in the mechanisms involved in the hypertension and deterioration of renal function in SD rats with prolonged HFD and ARDev. The role of angiotensin II (Ang II) in the arterial pressure (AP) increments, the renal hemodynamic sensitivity to Ang II, glomerular damage and changes in fat abdominal volume, plasma adipokine levels, renal NADPHp67phox expression, and renal infiltration of immune cells were examined. Hypertension and deterioration of renal function were enhanced (P < 0.05) in both sexes of rats with HFD and ARDev. The decrease (P < 0.05) of AP elicited by candesartan in hypertensive rats was similar to that induced by the simultaneous administration of candesartan and apocynin. The greater (P < 0.05) renal vasoconstriction induced by Ang II in both sexes of rats with HFD and ARDev was accompanied by an enhanced (P < 0.05) infiltration of CD-3 cells and macrophages in the renal cortex and renal medulla. The increments (P < 0.05) in the renal expression of NADPHp67phox and glomeruloesclerosis were greater (P < 0.05) in males than in females with HFD and ARDev. Our results suggest that the hypertension and deterioration of renal function induced by HFD in rats with ARDev are Ang II-dependent and mediated by increments in oxidative stress and immune system activation. Sex-dependent increments in oxidative stress and glomerular damage may contribute to the deterioration of renal function in these rats.
Asunto(s)
Dieta Alta en Grasa , Hipertensión/fisiopatología , Enfermedades Renales/fisiopatología , Riñón , Factores Sexuales , Animales , Femenino , Riñón/fisiopatología , Masculino , Estrés Oxidativo , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To examine whether the cardiac, renal and uterine physiological hemodynamic changes during gestation are altered in rats with an early and prolonged exposure to a high fat diet (HFD). METHODS: Arterial pressure and cardiac, renal, uterine and radial arteries hemodynamic changes during gestation were examined in adult SD rats exposed to normal (13%) (n = 8) or high (60%) (n = 8) fat diets from weaning. Plethysmography, high-resolution high-frequency ultrasonography and clearance of an inulin analog were used to evaluate the arterial pressure and hemodynamic changes before and at days 7, 14 and 19 of gestation. RESULTS: Arterial pressure was higher (P<0.05) in rats with high than in those with normal (NFD) fat diet before pregnancy (123 ±3 and 110 ±3 mmHg, respectively) and only decreased at day 14 of gestation in rats with NFD (98±4 mmHg, P<0.05). A significant increment in stroke volume (42 ±10%) and cardiac output (51 ±12%) was found at day 19 of pregnancy in rats with NFD. The changes in stroke volume and cardiac output were similar in rats with NFD and HFD. When compared to the values obtained before pregnancy, a transitory elevation in renal blood flow was found at day 14 of pregnancy in both groups. However, glomerular filtration rate only increased (P<0.05) in rats with NFD at days 14 (20 ±7%) and 19 (27 ±8%) of gestation. The significant elevations of mean velocity, and velocity time integral throughout gestation in radial (127 ±26% and 111 ±23%, respectively) and uterine (91 ±16% and 111 ±25%, respectively) arteries of rats with NFD were not found in rats with an early and prolonged HFD. SUMMARY: This study reports novel findings showing that the early and prolonged exposure to a HFD leads to a significant impairment in the renal, uterine and radial arteries hemodynamic changes associated to gestation.
Asunto(s)
Arterias/fisiopatología , Vasos Coronarios/fisiopatología , Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Arterias/diagnóstico por imagen , Presión Sanguínea/fisiología , Vasos Coronarios/diagnóstico por imagen , Femenino , Tasa de Filtración Glomerular/fisiología , Riñón/irrigación sanguínea , Modelos Animales , Embarazo , Ratas , Flujo Sanguíneo Regional/fisiología , Volumen Sistólico/fisiología , Ultrasonografía , Útero/irrigación sanguínea , Útero/diagnóstico por imagenRESUMEN
AIM OF THE STUDY: During type 2 diabetes (T2D) and hypertension there is stimulation of renal proximal tubule angiotensinogen (AGT), but whether urinary excretion of AGT (uAGT) is an indicator of glomerular damage or intrarenal RAS activation is unclear. We tested the hypothesis that elevations in uAGT can be detected in the absence of albuminuria in a mouse model of T2D. METHODS: Male C57BL/6 mice (Nâ¯=â¯10) were fed a high fat (HFD; 45% Kcal from fat) for 28â¯weeks, and the metabolic phenotype including body weight, blood pressures, glucose, insulin, ippGTT, HOMA-IR, and cholesterol was examined. In addition, kidney Ang II content and reactive oxygen species (ROS) was measured along with urinary albumin, creatinine, Ang II, and AGT. RESULTS: All parameters consistent with T2D were present in mice after 12-14â¯weeks on the HFD. Systolic BP increased after 18â¯weeks in HFD but not NFD mice. Intrarenal ROS and Ang II concentrations were also increased in HFD mice. Remarkably, these changes paralleled the augmentation uAGT excretion (3.66⯱â¯0.50 vs. 0.92⯱â¯0.13â¯ng/mg by week 29; Pâ¯<â¯0.01), which occurred in the absence of overt albuminuria. CONCLUSIONS: In HFD-induced T2D mice, increases in uAGT occur in the absence of overt renal injury, indicating that this biomarker accurately detects early intrarenal RAS activation.
Asunto(s)
Angiotensinógeno/orina , Diabetes Mellitus Tipo 2/fisiopatología , Sistema Renina-Angiotensina/fisiología , Albuminuria , Animales , Biomarcadores/orina , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Experimental/orina , Diabetes Mellitus Tipo 2/orina , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Hipertensión/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/complicacionesRESUMEN
This study examines whether the intake of a high-fat diet very early in life leads to changes in arterial pressure and renal function and evaluates whether the mechanisms involved in these changes are sex-dependent. Experiments were performed in male and female Sprague-Dawley rats fed a normal or high-fat diet from weaning to 4 mo of age. This exposure to a high-fat diet lead to an angiotensin II-dependent elevation in arterial pressure and to significant increments in fat abdominal volume and plasma leptin that were similar in both sexes. In addition, the angiotensin II-induced increment in renal vascular resistance was greater ( P < 0.05) in male (106 ± 14%) and female (97 ± 15%) rats fed a high-fat diet than in rats fed a normal-fat diet (51 ± 8%). However, the high-fat intake during early life induced increments in albuminuria, interleukin-6, and infiltration of CD3 lymphocytes in the renal parenchyma that were greater ( P < 0.05) in male than in female rats. Other sex-dependent differences in response to high-fat intake were that adiponectin levels only decreased in females (21%, P < 0.05), and renal NF-κB expression only increased in males (31%, P < 0.05). In summary, the early exposure to a high-fat diet leads to angiotensin II-dependent arterial pressure elevations and to increments in abdominal fat and in the renal sensitivity to angiotensin II that are similar in both sexes. However, the mechanisms involved in the renal changes associated with early exposure to a high-fat diet are different in males and females.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hipertensión/etiología , Enfermedades Renales/etiología , Riñón/fisiopatología , Obesidad/etiología , Grasa Abdominal/fisiopatología , Adipoquinas/sangre , Adiposidad , Factores de Edad , Albuminuria/etiología , Albuminuria/fisiopatología , Angiotensina II/toxicidad , Animales , Presión Arterial , Progresión de la Enfermedad , Femenino , Hipertensión/sangre , Hipertensión/fisiopatología , Mediadores de Inflamación/sangre , Riñón/metabolismo , Enfermedades Renales/sangre , Enfermedades Renales/fisiopatología , Masculino , Obesidad/sangre , Obesidad/fisiopatología , Ratas Sprague-Dawley , Factores Sexuales , Factores de TiempoRESUMEN
Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANG II-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Na+ handling remains controversial. In the present study, we investigate the role of PRR in the regulation of renal function and BP by using a mouse model with specific deletion of PRR in the CD (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng·kg-1·min-1), the increases in systolic BP and diastolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved αENaC and γENaC, as well as lower ANG II and renin content in urine compared with wild-type mice. In isolated CD from CDPRR-KO mice, patch-clamp studies demonstrated that ANG II-dependent stimulation of ENaC activity was reduced because of fewer active channels and lower open probability. These data indicate that CD PRR contributes to renal function and BP responses during chronic ANG II infusion by enhancing renin activity, increasing ANG II, and activating ENaC in the distal nephron segments.
Asunto(s)
Angiotensina II , Presión Sanguínea , Hipertensión/metabolismo , Túbulos Renales Colectores/metabolismo , Natriuresis , ATPasas de Translocación de Protón/deficiencia , Receptores de Superficie Celular/deficiencia , Eliminación Renal , Sodio/metabolismo , Animales , Modelos Animales de Enfermedad , Canales Epiteliales de Sodio/metabolismo , Predisposición Genética a la Enfermedad , Hipertensión/genética , Hipertensión/fisiopatología , Hipertensión/prevención & control , Túbulos Renales Colectores/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Proteinuria/metabolismo , Proteinuria/fisiopatología , ATPasas de Translocación de Protón/genética , Receptores de Superficie Celular/genética , Renina/metabolismo , Cloruro de Sodio Dietético/administración & dosificación , Cloruro de Sodio Dietético/metabolismo , Factores de TiempoRESUMEN
Numerous studies have evaluated blood pressure (BP) and renal changes in several models of developmental programming of hypertension. The present study examined to what extent BP, renal hemodynamic, and renal structure are affected at an old age in male and female animals with altered renal development. It also evaluated whether renal damage is associated with changes in cyclooxygenase (COX)-2 and neuronal nitric oxide synthase (NOS1) expression and immunoreactivity. Experiments were carried out in rats at 10-11 and 16-17 mo of age treated with vehicle or an ANG II type 1 receptor antagonist during the nephrogenic period (ARAnp). A progressive increment in BP and a deterioration of renal hemodynamics were found in both sexes of ARAnp-treated rats, with these changes being greater (P < 0.05) in male rats. The decrease in glomerular filtration rate at the oldest age was greater (P < 0.05) in male (74%) than female (32%) ARAnp-treated rats. Sex-dependent deterioration of renal structure was demonstrated in optical and electron microscopic experiments. COX-2 and NOS1 immunoreactivity were enhanced in the macula densa of male but not female ARAnp-treated rats. The present study reports novel findings suggesting that stimuli that induce a decrease of ANG II effects during renal development lead to a progressive increment in BP and renal damage at an old age in both sexes, but these BP and renal changes are greater in males than in females. The renal damage is associated with an increase of COX-2 and NOS1 in the macula densa of males but not females with altered renal development.
Asunto(s)
Envejecimiento/fisiología , Hipertensión/fisiopatología , Óxido Nítrico Sintasa de Tipo I/biosíntesis , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Ciclooxigenasa 2/metabolismo , Femenino , Tasa de Filtración Glomerular/fisiología , Hipertensión/etiología , Imidazoles/farmacología , Masculino , Óxido Nítrico Sintasa de Tipo I/metabolismo , Ratas , Ratas Sprague-Dawley , Caracteres Sexuales , Tetrazoles/farmacologíaRESUMEN
This study was performed to test the hypothesis that ANG II contributes to the hypertension and renal functional alterations induced by a decrease of COX2 activity during the nephrogenic period. It was also examined whether renal functional reserve and renal response to volume overload and high sodium intake are reduced in 3-4- and 9-11-mo-old male and female rats treated with vehicle or a COX2 inhibitor during nephrogenic period (COX2np). Our data show that this COX2 inhibition induces an ANG II-dependent hypertension that is similar in male and female rats. Renal functional reserve is reduced in COX2np-treated rats since their renal response to an increase in plasma amino acids levels is abolished, and their renal ability to eliminate a sodium load is impaired (P < 0.05). This reduction in renal excretory ability is similar in both sexes during aging but does not induce the development of a sodium-sensitive hypertension. However, the prolonged high-sodium intake at 9-11 mo of age leads to a greater proteinuria in male than in female (114 ± 12 µg/min vs. 72 ± 8 µg/min; P < 0.05) COX2np-treated rats. Renal hemodynamic sensitivity to acute increments in ANG II is unaltered in both sexes and at both ages in COX2np-treated rats. In summary, these results indicate that the reduction of COX2 activity during nephrogenic period programs for the development of an ANG II-dependent hypertension, reduces renal functional reserve to a similar extent in both sexes, and increases proteinuria in males but not in females when there is a prolonged increment in sodium intake.
Asunto(s)
Envejecimiento/fisiología , Angiotensina II/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Hipertensión/fisiopatología , Riñón/metabolismo , Masculino , Proteinuria/metabolismo , Ratas , Ratas Sprague-Dawley , Caracteres SexualesRESUMEN
It is known that cyclooxygenase-2 (COX-2) inhibition elicits significant renal hemodynamics alterations when sodium intake is low. However, the mechanisms involved in these renal changes are not well known. Our objective was to evaluate the role of angiotensin II and 5-lipooxygenase-derived metabolites in the renal effects induced by prolonged COX-2 inhibition when sodium intake is low. Conscious dogs were treated during 7 days with a COX-2 inhibitor (1 mg·kg·d, SC75416), and either a vehicle, an AT1 receptor antagonist (0.4 mg · kg · d, candesartan) or a selective 5-lipooxygenase inhibitor (PF-150, 20 and 60 mg · kg · d). The administration of SC75416 alone induced significant changes in renal blood flow (219 ± 14 to 160 ± 10 mL/min), glomerular filtration rate (51 ± 2 to 42 ± 3 mL/min), and plasma potassium (pK) (4.3 ± 0.1 to 4.6 ± 0.1 mEq/L). Similar decrements in renal blood flow (27%) and glomerular filtration rate (20%) and a similar increment in pK (7%) were found when SC75416 was administered in candesartan-pretreated dogs. However, SC75416 administration did not elicit significant changes in renal hemodynamics and pK in dogs pretreated with each dose of PF-150. Our data suggest that leukotrienes but not angiotensin II are involved in the renal effects induced by COX-2 inhibition when sodium intake is low.
Asunto(s)
Angiotensina II/metabolismo , Ciclooxigenasa 2/metabolismo , Dieta Hiposódica , Leucotrienos/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Bencimidazoles/farmacología , Benzopiranos/farmacología , Compuestos de Bifenilo , Ciclooxigenasa 2/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Perros , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/metabolismo , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/farmacología , Piranos/administración & dosificación , Piranos/farmacología , Pirazoles/administración & dosificación , Pirazoles/farmacología , Circulación Renal/efectos de los fármacos , Tetrazoles/farmacologíaRESUMEN
Numerous studies have demonstrated that angiotensin II (ANG II) is involved in hypertension and renal changes occurring as a consequence of an adverse event during renal development. However, it was unknown whether this involvement is sex and age dependent. This study examines whether the increments in arterial pressure (AP) and in the renal sensitivity to ANG II are sex and age dependent in rats with altered renal development. It also evaluates whether the ANG II effects are accompanied by increments in AT(1) receptors and oxidative stress. Experiments were performed in 3- to 4- and 10- to 11-mo-old rats treated with vehicle or an AT(1) receptor antagonist (ARAnp) during the nephrogenic period. ARAnp-treated rats were hypertensive, but an age-dependent rise in AP was only found in males. Three days of treatment with candesartan (7 mg·kg(-1)·day(-1)) led to a fall of AP that was greater (P < 0.05) in male than in female 10- to 11-mo-old ARAnp-treated rats. Oxidated proteins were elevated (P < 0.05), and the decrease in AP elicited by candesartan was reduced (P < 0.05) when these rats are also treated with tempol (18 mg·kg(-1)·day(-1)). Hypertension was not maintained by an elevation of AT(1) receptors in kidneys and mesenteric arteries. The acute renal hemodynamic response to ANG II (30 ng·kg(-1)·min(-1)) was similarly enhanced (P < 0.05) in both sexes of ARAnp-treated rats at 3-4 but not at 10-11 mo of age. Our results suggest that an adverse event during the nephrogenic period induces an ANG II-dependent increment in AP that is aggravated only in males during aging and that oxidative stress but not an increase in AT(1) receptor contributes to the rise in AP. This study also shows that the renal hemodynamic sensitivity to ANG II is transitorily enhanced in both sexes of rats with altered renal development.
Asunto(s)
Angiotensina II/fisiología , Presión Arterial , Riñón/crecimiento & desarrollo , Envejecimiento/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Presión Arterial/efectos de los fármacos , Bencimidazoles/farmacología , Compuestos de Bifenilo , Femenino , Riñón/efectos de los fármacos , Masculino , Arterias Mesentéricas/fisiopatología , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/fisiología , Caracteres Sexuales , Tetrazoles/farmacologíaRESUMEN
Cyclooxygenase 2 (COX2) is involved in regulating renal hemodynamics after renal ablation. It is also known that high protein intake (HPI) leads to a deterioration of renal function when there is preexisting renal disease and that there are important gender differences in the regulation of renal function. This study tested the hypothesis that the role of COX2 in regulating renal function and the renal hemodynamic effects elicited by HPI are enhanced when nephrogenesis is altered during renal development. It was also expected that the role of COX2 and the effects elicited by HPI are age and sex dependent. Newborn Sprague-Dawley rats were treated with an AT(1) ANG II receptor antagonist during the nephrogenic period (ARAnp). Experiments were performed at 3-4 and 10-11 mo of age. Arterial pressure was elevated (P < 0.05) at both ages and in both sexes of ARAnp-treated rats. Renal COX2 expression was only elevated (P < 0.05) at 10-11 mo of age in both sexes of ARAnp-treated rats. COX2 inhibition induced greater renal vasoconstriction in male and female hypertensive than in normotensive rats at both ages. HPI did not induce glomerular filtration rate (GFR) in the youngest hypertensive rats and in the oldest female hypertensive rats. However, the GFR decreased during HPI (0.63 ± 0.07 to 0.19 ± 0.05 ml/min) in the oldest male hypertensive rats. The HPI-induced increment in proteinuria was greater (P < 0.05) in male (99 ± 22 mg/day) than in female (30 ± 8 mg/day) hypertensive rats. These results show that COX2 plays an important role in the regulation of renal function when renal development is altered and that prolonged HPI can lead to a renal insufficiency in males but not in females with reduced nephron endowment.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Proteínas en la Dieta/efectos adversos , Riñón/enzimología , Organogénesis , Insuficiencia Renal/etiología , Animales , Animales Recién Nacidos , Inhibidores de la Ciclooxigenasa 2/farmacología , Femenino , Riñón/crecimiento & desarrollo , Masculino , Óxido Nítrico Sintasa de Tipo I/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Caracteres SexualesRESUMEN
Several studies have proposed that cyclooxygenase-2 (COX2) is involved in the regulation of nephrogenesis and that an impaired nephrogenesis may induce the development of hypertension. This study was designed to test the hypothesis that the decrease of COX2 activity leads to a reduction in nephron number, an increase in arterial pressure, and age-dependent renal alterations that are greater in male than in female rats. Arterial pressure was measured from the first to the 16th month of life in rats treated with vehicle or a COX2 inhibitor during the nephrogenic period. Stereological and histological evaluations and renal function studies were performed at different ages. Arterial pressure increased (14%; P<0.05) and nephron number decreased (17%; P<0.05) to similar levels in male and female COX2-treated rats. However, glomerular filtration rate (31%) and renal plasma flow (25%) decreased (P<0.05) in male but not in female COX2-treated rats. A greater (P<0.05) age-dependent elevation in glomerular hypertrophy was also found in male COX2-treated rats compared with their female littermates. Glomerulosclerosis and tubulointerstitial damage in renal cortex and medulla were also significantly enhanced in male but not in female aged COX2-treated rats. Our results demonstrate that the decrease in COX2 activity during renal development leads to a reduction in nephron number and to an elevation in arterial pressure that are similar in males and females. However, the consequent age-dependent deterioration of the renal structure and renal function is only significantly enhanced in male rats.
Asunto(s)
Envejecimiento/metabolismo , Ciclooxigenasa 2/metabolismo , Hipertensión/enzimología , Glomérulos Renales/enzimología , Nefronas/embriología , Nefronas/enzimología , Caracteres Sexuales , Envejecimiento/patología , Animales , Presión Sanguínea/fisiología , Peso Corporal , Femenino , Tasa de Filtración Glomerular/fisiología , Hipertensión/etiología , Hipertensión/patología , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/patología , Masculino , Nefronas/patología , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/fisiologíaRESUMEN
We have demonstrated that the reduction of angiotensin II effects during the nephrogenic period reduces the nephron number and induces the development of hypertension. The hypotheses examined are that this reduction of angiotensin effects leads to the development of an age-dependent sodium sensitive hypertension and that the hypertension is angiotensin II dependent. Newborn rats were treated with an angiotensin II type 1 receptor antagonist during the first 2 weeks of age. At 3 to 4 and 11 to 12 months of age, changes in systolic blood pressure, proteinuria, and renal function in response to a prolonged high sodium intake were examined. The basal blood pressure response to the administration of the angiotensin II receptor antagonist was also evaluated at both ages. Basal blood pressure was similarly elevated (P<0.05) in male and female treated rats, and the increment was age dependent. High sodium intake only elicited a blood pressure elevation (136+/-1 to 154+/-3 mm Hg; P<0.05) and a decrease in glomerular filtration rate (28%; P<0.05) at 11 to 12 months in treated rats. Blockade of angiotensin II receptors during renal development induced an increase (P<0.05) in proteinuria that was age and sex dependent, but high sodium intake only induced an elevation in proteinuria in the younger rats (50%; P<0.05). Hypertension was maintained by angiotensin II at both ages because blood pressure decreased to normal levels after treatment with an angiotensin II type 1 receptor antagonist. This study shows that the reduction of angiotensin II effects during the nephrogenic period modifies renal function and induces the development of an angiotensin II-dependent hypertension that becomes sodium sensitive during aging.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Hipertensión Renal/patología , Nefronas/efectos de los fármacos , Nefronas/patología , Cloruro de Sodio Dietético/farmacología , Factores de Edad , Angiotensina II/metabolismo , Animales , Animales Recién Nacidos , Proteínas en la Dieta/farmacología , Modelos Animales de Enfermedad , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Hipertensión Renal/inducido químicamente , Hipertensión Renal/tratamiento farmacológico , Masculino , Nefronas/crecimiento & desarrollo , Proteinuria/patología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/metabolismo , Factores SexualesRESUMEN
The aim was to evaluate whether blockade of ANG II effects during renal development modifies the renal response to an increment of plasma amino acid concentration. It was also examined in anesthetized rats whether the reduction of the renal ability to eliminate an acute volume expansion (VE), elicited by blockade of ANG II during renal development, is sex and/or age dependent. Newborn Sprague-Dawley rats were treated with vehicle or an AT(1)-receptor antagonist (ARA) during postnatal nephrogenesis. Amino acid infusion induced increments (P < 0.05) of glomerular filtration rate (31 +/- 6%) and renal plasma flow (26 +/- 5%) in male but not in female vehicle-treated rats. Natriuretic and diuretic responses to amino acid infusion were similar in male and female vehicle-treated rats. These renal hemodynamics and excretory responses to amino acid infusion were abolished in ARA-treated rats. Renal responses to VE were evaluated at 3-4 and 9-10 mo of age in vehicle and ARA-treated rats. VE-induced natriuresis and diuresis were reduced by more than 38% (P < 0.05) in 3- to 4-mo-old male and female ARA-treated rats. An age-dependent reduction (P < 0.05) in the renal ability to eliminate VE was found in male but not in female rats treated with ARA. Our results demonstrate that the renal effects induced by an increment in amino acids are abolished when ANG II effects have been reduced during nephrogenesis. In addition, this reduction of ANG II effects elicits an impairment of the renal ability to eliminate an acute VE in males and females, which is aggravated by age only in male rats.
Asunto(s)
Angiotensina II/sangre , Riñón/irrigación sanguínea , Riñón/crecimiento & desarrollo , Circulación Renal/fisiología , Factores de Edad , Aminoácidos/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Animales Recién Nacidos , Volumen Sanguíneo/fisiología , Diuresis/efectos de los fármacos , Diuresis/fisiología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Soluciones Isotónicas/farmacología , Masculino , Natriuresis/efectos de los fármacos , Natriuresis/fisiología , Embarazo , Ratas , Ratas Sprague-Dawley , Circulación Renal/efectos de los fármacos , Factores SexualesRESUMEN
This study was designed to test the hypothesis that blockade of angiotensin II effects during renal development accelerates the aging-related changes in renal hemodynamics and proteinuria, and that these changes are sex dependent. It has also been examined whether the deterioration of urinary concentrating ability elicited by angiotensin II blockade is sex and/or aging dependent. Newborn Sprague-Dawley rats were treated with vehicle or an AT(1) angiotensin II receptor antagonist (ARA) during the first 14 postnatal days. Blood pressure, glomerular filtration rate, proteinuria, and urinary concentrating ability in response to dehydration were examined in conscious rats at 3 and 11 mo of age. ARA treatment elicited a similar increment in blood pressure in males and females that was greater (P < 0.05) at 11 than at 3 mo of age. Glomerular filtration rate only decreased (P < 0.05) in 11-mo-old male ARA-treated rats (0.59 +/- 0.07 vs. 0.80 +/- 0.07 ml.min(-1).g(-1) in control group). At 3 mo of age, proteinuria increased in male (107%) but not in female ARA-treated rats. However, at 11 mo of age, proteinuria increased in both sexes, but the increment was greater (P < 0.05) in male (244%) than in female (138%) ARA-treated rats. Renal ability to concentrate urine in response to prolonged water dehydration was only reduced in ARA-treated males. The reduction of urinary concentrating ability was accentuated by aging. Therefore, we conclude that blockade of angiotensin II effects during renal development elicits an important deterioration of cortical and medullary function that is sex and aging dependent.
Asunto(s)
Envejecimiento/fisiología , Angiotensina II/fisiología , Riñón/crecimiento & desarrollo , Angiotensina II/antagonistas & inhibidores , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Animales Recién Nacidos , Presión Sanguínea/fisiología , Peso Corporal/fisiología , Creatinina/metabolismo , Deshidratación/metabolismo , Femenino , Tasa de Filtración Glomerular/fisiología , Riñón/fisiología , Masculino , Concentración Osmolar , Embarazo , Proteinuria/metabolismo , Ratas , Ratas Sprague-Dawley , Circulación Renal/fisiología , Caracteres SexualesRESUMEN
The renin-angiotensin system plays an important role in renal development. However, it is unknown whether reduction in angiotensin II effects during the nephrogenic period leads to different renal alterations in males and females during the adult age. The aim of this study was to evaluate whether the role of angiotensin II on renal development is sex dependent and whether there are sex differences in blood pressure, renal hemodynamics, and severity of renal damage during adult life when nephrogenesis is altered by blocking angiotensin II effects. Newborn Sprague-Dawley rats were treated with an angiotensin II type 1 receptor antagonist (L-158.809; 7 mg/kg per day) during the first 2 weeks of life. At 3 months of age, changes in blood pressure, albuminuria, and renal hemodynamics were assessed, and stereological and histopathologic studies were performed. Blood pressure increased (127+/-0.5 versus 115+/-0.7 mm Hg in control rats; P<0.05) and nephron number decreased (37%; P<0.05) similarly in treated males and females. However, only males had an elevation in albuminuria (5.92+/-1.65 versus 0.33+/-0.09 mg per day in control rats; P<0.05), a fall in glomerular filtration rate (12.6%; P<0.05), and a significant decrease in papillary volume (42%; P<0.05). Mean glomerular volume, glomerulosclerosis, arteriolar hypertrophy, and tubulointerstitial damage in cortex and medulla were also higher (P<0.05) in angiotensin II type 1 receptor antagonist-treated males than in treated females. The results of this study suggest that females seem to be more protected than males to the renal consequences of reducing angiotensin II effects during renal development.