Membrane and soluble forms of endoglin in preeclampsia.

Preeclampsia is a disease of high incidence in pregnant women which complicates pregnancy and may lead to the death of mother and baby. Preeclampsia is characterized by a series of clinical features such as hypertension and proteinuria associated with endothelial dysfunction. Although the causes of disease have not been elucidated, it has been reported that high levels of endoglin, a TGF-ß auxiliary co-receptor, and a soluble form of this protein, occur respectively in the placenta and plasma of women who develop the disease. In this review, the alterations in vasculogenesis and angiogenesis that occur during preeclampsia, the cellular and molecular mechanisms that lead to increased membrane bound endoglin expression and soluble endoglin release, including hypoxia and oxidative stress, and the possible pathogenic role of soluble endoglin in this disease have been analyzed.

Effects and mechanism of organ protection by cardiotrophin-1.

Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1 on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although many effects of CT-1 have been described on the heart, CT-1 has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFRß) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated.

La exposición crónica al uranio, un riesgo potencial de nefrotoxicidad / Uranium is a naturally occurring element widely distributed in the crust

El uranio es un elemento natural que se encuentra ampliamente distribuido en la corteza terrestre. Cierta cantidad de este metal se encuentra presente en los alimentos, en el aire, en el suelo y en el agua, por lo que el ser humano se encuentra expuesto al mismo de forma natural. Pero también puede ser objeto de una sobreexposición patológica como consecuencia de la deposición de uranio natural desde la atmósfera o debido a actividades industriales humanas que vierten productos de desecho directamente sobre el terreno. Actualmente la exposición debida a la actividad industrial se ha incrementado debido a que el uranio representa una de las pocas fuentes energéticas que cumplen con el “Protocolo de Kyoto”, sumándole la ventaja de que es muy económico. España, es uno de los países Europeos con más contenido de uranio en su suelo y por ello, susceptible de exposición natural, pero también industrial, ya que dada la demanda energética se están reabriendo algunas de sus minas. La nefrotoxicidad es el principal efecto observado tras exposición aguda a uranio. Este efecto se ha descrito en múltiples estudios realizados en animales de experimentación y en algunos casos de humanos expuestos a dosis elevadas de uranio de forma accidental. Sin embargo, la producción de daño renal por exposición crónica está poco documentada. Existen escasos estudios experimentales en los que se administren bajas dosis de uranio durante largos periodos de tiempo y los referidos en humanos son muy heterogéneos en cuanto a la vía de exposición, la dosis, el tipo de uranio etc, por lo que resulta muy difícil extraer conclusiones sobre los efectos renales por sobreexposición crónica. En esta revisión se pretende hacer una recopilación y discusión de gran parte de estudios epidemiológicos y de experimentación, a fin de obtener una idea de la nefrotoxicidad real que supone la exposición crónica a este metal para el ser humano (AU)

Certain amount of this metal is present in food, air, soil and water, for that humans are exposed to it naturally. But it can also be pathological overexposure as a result of natural uranium deposition from the atmosphere or due to human industrial activities that discharge waste products directly on the ground. Currently exposure due to industrial activity has increased because the uranium is one of the few sources of energy that meet the "Kyoto Protocol", adding the advantage that it is very economical. Spain is one of most European countries with uranium content in soil and thus susceptible to natural exposure, but also industrial, as given energy demand are reopening some of its mines. Nephrotoxicity is the main effect observed after acute exposure to uranium. This effect has been described in multiple studies in experimental animals and in some cases of humans accidentally exposed to high doses of uranium. However, the production of kidney damage from chronic exposure is poorly documented. There are few experimental studies in which low doses are administered uranium for long periods of time. Moreover, data in humans are very heterogeneous regarding the route of exposure, dose, type of uranium etc, so it is very difficult to draw findings on chronic renal effects of overexposure. In this review we tried to make a compilation and discussion of several epidemiological and experimental studies in order to get an idea of the real nephrotoxicity involving chronic exposure to this metal to humans (AU)

Osteoprotegerin and diabetes-associated pathologies.

Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor superfamily of cytokines which, in spite of being initially described as a strong anti-resorptive factor, has lately been considered as a possible link between bone and vascular disease. In the last few years, several studies have evidenced its close relationship with the development of diabetes. In this review, we analyse the role of OPG in diabetic patients and its links with the most relevant associated diseases such as atherosclerosis, hypertension, endothelial dysfunction and diabetic nephropathy, as well as its connection with related pathologies as fibrosis, obesity and metabolic syndrome.

Kidney androgen-regulated protein transgenic mice show hypertension and renal alterations mediated by oxidative stress.

BACKGROUND: Kidney androgen-regulated protein (KAP), a proximal tubule androgen-regulated gene, codes for a protein of unknown function. METHODS AND RESULTS: To investigate the consequences of KAP overexpression in kidney, we produced KAP transgenic mice and performed microarray expression analyses in kidneys of control and transgenic males. Downregulation of the androgen-sensitive Cyp4A14 monooxygenase gene in KAP transgenic mice prompted us to analyze blood pressure levels, and we observed that transgenic mice were hypertensive. Inhibition of 20-hydroxyeicosatetraenoic acid synthesis by N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) reduced the increased 20-hydroxyeicosatetraenoic acid levels in urine and normalized arterial pressure in transgenic mice, as did the NADPH oxidase inhibitor apocynin. Increased oxidative stress in transgenic mice was demonstrated by (1) enhanced excretion of urinary markers of oxidative stress, 8-iso-prostaglandin F2alpha, 8-hydroxydeoxyguanosine, and thiobarbituric acid-reacting substances; (2) augmented mitochondrial DNA damage and malondialdehyde levels in kidneys; and (3) diminished catalase and glutathione peroxidase activity in transgenic kidneys. Mice exhibited renal defects that included focal segmental glomerulosclerosis, proteinuria, glycosuria, and fibrosis. CONCLUSIONS: Taken together, these results indicate that KAP expression is critical for cardiovascular-renal homeostasis maintenance and that hypertension is associated with increased oxidative stress. This is the first report showing that overexpression of an androgen-regulated, proximal tubule-specific gene induces hypertension. These observations may shed light on the molecular pathophysiology of gender differences in the prevalence and severity of hypertension and chronic renal disease.

Teaching integrative physiology using the quantitative circulatory physiology model and case discussion method: evaluation of the learning experience.

One of the problems that we have found when teaching human physiology in a Spanish medical school is that the degree of understanding by the students of the integration between organs and systems is rather poor. We attempted to remedy this problem by using a case discussion method together with the Quantitative Circulatory Physiology (QCP) program. QCP is a Windows-based computer simulation program that offers almost real-time simulation and allows users to examine the time-dependent interactions of over 750 parameters. We evaluated students' perceptions by an anonymous questionnaire. Teachers' perceptions of this teaching approach were highly positive, as it improved students' perceptions of the complexity of biological processes, their ability to differentiate between acute and chronic responses, and promoted an integrative understanding of human body function. Teachers also identified some problems with the approach, including student difficulties in adopting self-directed learning, a lack of precision in student questions during the discussion sessions, and the lack of a tradition of using several textbooks to explain the changes observed. The results of the student questionnaire revealed that >70% of the students reported that this type of learning gave them a better understanding of the complexity of physiological processes and the role of coordinated actions of several systems in the homeostatic response and enabled them to acquire a better understanding of human body functions. Thus, we conclude that this approach promotes an integrative understanding of cardiovascular and renal functions that is difficult to achieve with other methods.

Effect of the flavonoid quercetin on cadmium-induced hepatotoxicity.

The present study was designed to evaluate whether treatment with quercetin exerts any beneficial effect on cadmium (Cd)-induced hepatotoxicity in order to establish the possible protective mechanisms of quercetin. Wistar rats were distributed in four experimental groups: control, Cd, quercetin, and Cd+quercetin. Hepatic toxicity was evaluated by measuring plasma concentrations of markers of hepatic injury. The activity of antioxidant enzymes in liver was also measured. Hepatic expression of metallothioneins (MT), and endothelial nitric oxide synthase (eNOS) was assayed by Western and Northern blot. Our results demonstrated that Cd administration induced an increased marker enzyme activity in plasma. This effect was not inhibited by quercetin. However, the administration of quercetin softened Cd-induced oxidative damage. MT levels in liver were substantially increased when the animals received Cd and quercetin. Hepatic eNOS expression was significantly increased after treatment with Cd and quercetin, being this increase higher than in animals receiving Cd alone. In conclusion, in this experimental model, quercetin was not able to prevent the Cd-induced liver damage although the animals that received both, Cd and quercetin showed a marked improvement in oxidative stress and an increase in the MT and eNOS expression. These results suggest that other mechanisms different to oxidative stress could be involved in hepatic damage.

Involvement of small Ras GTPases and their effectors in chronic renal disease.

The mechanisms involved in the development of renal fibrosis are poorly understood. Small Ras GTPases control cell proliferation, differentiation, cellular growth and apoptosis, with cell-specific expression in the kidney. Cytokines, high glucose medium or advanced glycation end-products activate Ras in different renal cells. Increased Ras activation has been found in experimental tubulointerstitial fibrosis. Transforming growth factor-beta1 (TGF-beta1) and Ras signalling pathways are close related: TGF-beta1 overcomes Ras mitogenic effects, and Ras counteracts TGF-beta signalling. However, Ras activation is also an intracellular signal transduction point for several molecules (e.g. TGF-beta1) involved in kidney damage. Ras isoforms play different roles in regulating extracellular matrix synthesis in fibroblasts and mesangial cells. These data give evidence for a role for Ras in renal fibrosis, but no reviews are available on the role of p21 Ras in this process. Thus, our goal is to review the role of Ras activation and signalling in renal fibrosis.

Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties.

Oxidative stress can play a key role in Cd-induced dysfunctions. Quercetin is a potent oxygen free radicals scavenger and a metal chelator. Our aim was to study the effect of quercetin on Cd-induced kidney damage and oxidative stress as well as its mechanism of action. Wistar rats were distributed in four experimental groups: control rats; Cd; quercetin and Cd+quercetin. Renal toxicity was evaluated by measuring urinary excretion of proteins, albumin, glucose and enzymes markers of tubular necrosis, as well as plasma concentration of creatinine. Plasma TBARS concentration and activity of antioxidant enzymes in kidney were also measured. Renal cell damage was assessed by electron microscopy. Animals that received both Cd and quercetin showed a better renal function than those receiving Cd alone. Cd-induced tubular lesions were markedly reduced in rats that also received quercetin. Cd-induced increase in plasma TBARS was prevented by the administration of quercetin. Total plasma antioxidants and renal superoxide dismutase and glutathione-reductase activities were higher in the group that received Cd and quercetin than in rats that received Cd alone. Quercetin administration does not modify the renal content or the urinary excretion of Cd. In conclusion, quercetin treatment prevents renal tubular damage and increased oxidative stress induced by chronic Cd administration, most probably throughout its antioxidant properties.

TGF-beta1 induces COX-2 expression and PGE2 synthesis through MAPK and PI3K pathways in human mesangial cells.

Transforming growth factor-beta1 (TGF-beta1) plays a fundamental role in the progression of renal diseases. Accumulating evidence has suggested that eicosanoids derived from cyclooxygenase-2 (COX-2) participate in a number of pathological processes in immune-mediated renal diseases. Mesangial cells (MC) play a major role in physiological and pathophysiological renal processes. MC express receptors for TGF-beta1, and COX-2 expression can be induced in MC. However, to date, there are no published data on the possible role of TGF-beta1 in COX-2 expression in human mesangial cells (HMC). We designed studies to determine (1) whether TGF-beta1 stimulates COX-2 expression in primary HMC, (2) whether mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) cascades are involved in TGF-beta1-induced COX-2 expression, and (3) whether prostaglandin (PG)E2 synthesis is affected by TGF-beta1 and MAP kinases and PI3K activation. Studies were performed in primary cultures of HMC and in an immortalized line of HMC. TGF-beta1 induces COX-2 promoter activity and COX-2 mRNA and protein expression in HMC. COX-2 induction is accompanied by increased PGE2 synthesis. Extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and PI3K pathway inhibition blunted TGF-beta1-induced COX-2 overexpression. We demonstrate that TGF-beta1 regulates COX-2 expression in HMC through the activation of ERK1/2, p38 MAPK, and PI3K. These results can help to elucidate the molecular mechanisms underlying the regulation of COX-2 and open up specific strategies for the treatment of glomerular disease.

Ciclooxigenasas y función renal / Cyclooxygenases and renal function

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Estudio de farmacovigilancia para evaluar la seguridad y la efectividad del tratamiento con losartán: efectos a largo plazo de losartán solo o en combinación sobre la uricemia / Pharmacovigilance study of the safety and effectiveness of losartan therapy: long-term effects of losartan alone or in combination on uricemia

Introducción: se evalúa la acción del tratamiento con losartán sobre la uricemia, en pacientes hipertensos en el medio comunitario. Material y método: estudio de farmacovigilancia, observacional, prospectivo, multicéntrico, no aleatorizado, abierto, de 1 año de seguimiento. Centros de atención primaria de Ávila, Burgos, León, Palencia, Salamanca, Valladolid y Zamora. Se incluyó a 275 pacientes de 67,5 años, con hipertensión arterial, no diabéticos y diabéticos (n = 19), a los que se trató con losartán, 50 mg/día. A las 8 semanas se aumentaba a 100 mg/día si era preciso. Si a las 24 semanas la presión arterial (PA) persistía elevada, se añadía hidroclorotiazida, 25 mg. Se procedió a la toma de sangre para uricemia, creatinina, electrolitos, glucemia, colesterol y triglicéridos al comienzo y a las 48 semanas de tratamiento. Resultados: la uricemia disminuyó significativamente en el grupo de pacientes tratados con losartán y losartán + tiazidas. El 30% de los pacientes recibió 50 mg de losartán, el 14%, 100 mg y el 56%, losartán + tiazida. La PA media ± desviación estándar varió desde 166 ± 29 mmHg de sistólica y 96 ± 19 mmHg, al comienzo del estudio, a 145 ± 23 mmHg de sistólica y 83 ± 18 mmHg de diastólica al finalizarlo. La creatinina, el sodio, el potasio, la glucemia, el colesterol y los triglicéridos no sufrieron deterioro durante el año de seguimiento. Conclusiones: el losartán es un fármaco seguro, con pocos efectos secundarios y que, tras 1 año de seguimiento, disminuye la uricemia sin deterioro del perfil lipídico, hidrocarbonato ni renal. Se postula como fármaco de primera elección en hipertensos mayores con hiperuricemia

Objectives: to evaluate the effect of losartan therapy on uricemia in patients with hypertension in the community setting. Design: observational, prospective, multicenter, nonrandomized, open-label pharmacovigilance study with a 1-year follow-up. Setting: primary care centers in Avila, Burgos, Leon, Palencia, Salamanca, Valladolid, and Zamora (Spain). Patients and method: two hundred seventy-five men and women (mean age 67.5 years), without diabetes (n = 256) and with diabetes (n = 19), treated with 50 mg/day of losartan were included. If high blood pressure (BP) (> 140/90 mmHg) was uncontrolled at 8 weeks, the dose was increased to 100 mg/day. If BP continued to be high at 24 weeks, hydrochlorothiazide (25 mg) was added. BP was measured after the patient had been sitting for 7 minutes with a mercury manometer and phase V Korotkoff's sound as the reference point. Blood samples were drawn for analysis of uricemia, creatinine, electrolytes, glycemia, cholesterol, and triglycerides at the beginning of the study and after 48 weeks' treatment. Results: uricemia significantly decreased in the group of patients treated with losartan and losartan + thiazides. Thirty percent of the patients received 50 mg of losartan, 14% received 100 mg and 56% received losartan + thiazide. Systolic BP was reduced from 166 (SD 29) mmHg at the beginning of the study to 145 (SD 23) at the end of the study. Diastolic BP was reduced from 96 (SD 19) mmHg to 83 (SD 18) mmHg. No negative effects on creatinine, sodium, potassium, glycemia, cholesterol or triglyceride values were found during the 1-year follow-up. Conclusions: losartan is a safe drug with few adverse effects. After a 1-year follow-up, it reduces uricemia without producing negative effects on lipid, carbohydrate or renal profiles. Therefore, it could be used as a first-line drug in elderly patients with hypertension and hyperuricemia

Papel de la vía de Ras en un modelo de nefrotoxicidad inducida por cadmio. Efecto protector del antioxidante quercetina / Role of Ras signalling pathway in a model of cadmium-induced nephrotoxicity. Protective effect of the antioxidant quercetin

El cadmio (Cd) es un tóxico presente en el medio ambiente que afecta a los sistemas biológicos por varias rutas. Los mecanismos moleculares de su toxicidad no están bien definidos. Nosotros hemos demostrado recientemente en un modelo de administración crónica de Cd en ratas, que la quercetina, un potente “scavenger" de radicales libres de oxígeno, tiene un efecto protector sobre la nefrotoxicidad inducida por Cd. La potente actividad antioxidante de la quercetina pudiera ser la responsable de este efecto protector. Sin embargo, el Cd activa múltiples rutas de señalización relacionadas con respuestas celulares frente al estrés. Ras es un miembro de la familia de las pequeñas GTPasas, con una gran variedad de funciones que incluyen la regulación de genes de expresión y proliferación celular. Nuestro objetivo en este trabajo fue estudiar el efecto del cadmio y la quercetina en el proceso proliferativo relacionado con las vías de señalización mediadas por Ras. El estudio se realizó durante nueve semanas con ratas Wistar. Se dividieron en cuatro grupos: 1) Grupo control, 2) Grupo cadmio: 1,2 mg/Kg/día, s.c., 3) Grupo quercetina: 50 mg/Kg/día, i.p., 4) Grupo cadmio-quercetina: animales tratados con cadmio y quercetina a las dosis y vías de administración anteriormente descritas. Para valorar la toxicidad renal se determinó la excreción urinaria de proteínas y enzimas marcadoras de necrosis tubular, así como las concentraciones plasmáticas de creatinina y urea. La expresión y activación renal de Ras se evaluó mediante Western blot e inmunohistoquímica. La proliferación celular se determinó por detección del antígeno Ki-67. Los resultados mostraron que la co-administración de cadmio y quercetina mejoró la función renal alterada por la exposición a cadmio. Por otra parte, se observó una mayor activación de Ras y una mayor proliferación celular en los riñones de los animales tratados con cadmio. El tratamiento con quercetina redujo la activación renal de Ras y el número de células en proliferación. Nuestros resultados sugieren que el efecto protector de la quercetina sobre la nefrotoxicidad inducida por cadmio pudiera deberse a la inhibición de esta ruta de señalización (AU)

Cadmium (Cd) is an ubiquitous environmental toxicant that affects biological systems in various ways. The molecular mechanisms of its toxicity are not yet well defined. We have recently reported in an experimental model of chronic cadmium administration in rats, that quercetin, a potent oxygen free radical scavenger, has a protective effect on cadmium-induced nephrotoxicity. Quercetin´s strong antioxidant activity could be responsible for the protective effect. However, Cd activates multiple signal transduction pathways related to cellular responses to stress. Ras is a member of a family of small GTPases with a great variety of functions including regulation of gene expression and cell proliferation. Our aim in this work was to study the effect of Cd and quercetin on the proliferation related to Ras-mediated signal transduction pathways. Experiments were carried out in male Wistar rats during nine weeks. Rats were distributed in four experimental groups: 1) control rats; 2) cadmium group (1,2 mg Cd/Kg/day s.c.); 3) quercetin group (50 mg/Kg/day, i.p.) and 4) cadmium-quercetin group (Cd and quercetin at the same doses as in the groups 2 and 3 respectively). Renal toxicity was evaluated by measuring urinary excretion of proteins and enzyme markers of tubular necrosis, as well as plasma concentrations of creatinine and urea. Renal expression of Ras and Ras activation was assessed by Western blot and inmuhistochemistry. Assessment of cell proliferation was evaluated by detection of the Ki-67 antigen. Animals that received both Cd and quercetin showed a better renal function than those receiving Cd alone. On the other hand, Cd increased renal Ras activation and cell proliferation. Quercetin treatment reduced Ras activation and the number of cells in proliferation. Our results suggest that the protective effect of quercetin on cadmium-induced nephrotoxicity could be associated with the inhibition of Ras signal transduction pathway (AU)

Manejo de agua y sodio por el riñón senescente. Interpretación de una técnica de aclaramiento para su estudio funcional / Handling of water and sodium by the senescent kidney. Interpretation of a clearance technique for functional study

Los trastornos hidroelectrolíticos, particularmente las hiponatremias, son frecuentes en personas ancianas y, en general, achacadas a un síndrome de secreción inapropiada de hormona antidiurética. Si bien esto es lo más frecuente en adultos jóvenes, no es el caso en los ancianos, cuya causa más frecuente es una depleción real del sodio motivada por cierto grado de incompetencia de la parte gruesa de la rama ascendente del asa de Henle. La localización se hizo mediante una sobrecarga hiposalina y un estudio de aclaramientos utilizando la técnica de Chaimowitz, que describimos y comentamos en este trabajo

Hydroelectrolytic disorders, especially hyponatremias, are frequent in the elderly and are generally due to a syndrome of inappropriate antidiuretic hormone secretion. Although this is the most common cause in young adults, the most frequent cause in the elderly is Na depletion due to impaired competence of the thick ascending limb of Henle's loop. Localization was performed through hyposaline loading and clearance study using Chaimowitz's technique, which we describe and discuss in the present article

Temporal changes in renal endoglin and TGF-beta1 expression following ureteral obstruction in rats.

Chronic renal disease is characterized by the accumulation of extracellular matrix proteins in the kidney and a loss of renal function. Tubulointerstitial fibrosis has been reported to play an important role in the progression of chronic renal diseases. Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine playing a major contribution to fibrotic kidney disease. Endoglin is a membrane glycoprotein of the TGF-beta1 receptor system. The aim of this work was to determine the time-course expression of renal type I and IV collagens, endoglin and TGF-beta1 in a rat model of induced tubulointerstitial fibrosis at 1, 3, 10 and 17 days after unilateral ureteral obstruction (UUO). In 17 days-ligated (L)-renal samples, a marked interstitial fibrosis was detected by Masson's trichromic and Sirius red staining, accompanied by an increase in type I collagen expression as shown by immunohistochemical analysis. Northern blot studies revealed a progressive increase in collagen alpha2(I), TGF-beta1 and endoglin mRNA expression in L kidneys when compared with the corresponding non-ligated (NL) kidneys from the animals subjected to left UUO. Seventeen days after UUO, significant increases in collagen alpha2(I), collagen alpha1(IV), TGF-beta1 and endoglin mRNA levels were detected in L kidneys vs NL kidneys. Significantly higher levels of the protein endoglin were found in L kidneys than in NL kidneys 10 and 17 days following obstruction. A marked increase expression for endoglin and TGF-beta1 was localized in renal interstitium by immunohistochemical studies 17 days after obstruction. In conclusion, this work reports the upregulation of endoglin coincident to that of its ligand TGF-beta1 in the kidneys of rats with progressive tubulointerstitial fibrosis induced by UUO.

Endoglin regulates nitric oxide-dependent vasodilatation.

Endoglin is a membrane glycoprotein that plays an important role in cardiovascular development and angiogenesis. We examined the role of endoglin in the control of vascular tone by measuring nitric oxide (NO)-dependent vasodilation in haploinsufficient mice (Eng+/-) and their Eng+/+ littermates. The vasodilatory effect of acetylcholine, bradykinin, and sodium nitroprusside was assessed in anesthetized mice; in isolated, perfused hindlimbs; and in aortic rings. The substantial hypotensive and vasodilatory response induced by acetylcholine and bradykinin in Eng+/+ was markedly reduced in Eng+/- mice. Both kinds of animals had similar responses to sodium nitroprusside, suggesting that the deficient vasodilatory effect is not due to a NO response impairment. Urinary and plasma concentrations of nitrites, a NO metabolite, were lower in Eng+/- than in Eng+/+ mice. The levels of endothelial nitric oxide synthase (eNOS) in kidneys and femoral arteries were about half in Eng+/- than in Eng+/+ mice and were also reduced in primary cultures of aortic endothelial cells from Eng+/- compared with those from Eng+/+ mice. Furthermore, overexpression or suppression of endoglin in cultured cells induced a marked increase or decrease in the protein levels of eNOS, respectively. Thus, our results in vivo and in vitro demonstrate a relationship between endoglin and NO-dependent vasodilation mediated by the regulation of eNOS expression.

Efecto de la quercetina sobre la nefrotoxicidad producida por cadmio / Effect of quercetin in cadmium-induced nephrotoxicity

El incremento en la producción anual de cadmio ha favorecido que la incidencia de la intoxicación crónica por este elemento haya aumentado en los últimos años. El estrés oxidativo es uno de los mecanismos implicados en la generación del efecto tóxico, manifestándose, entre otras patologías, por una disfunción y lesión renal. La quercetina, un flavonoide muy abundante en la dieta mediterránea, es un potente antioxidante y un buen quelante de metales. Nuestro objetivo fue estudiar si la administración de quercetina pudiera prevenir la aparición de los procesos nefrotóxicos asociados a la exposición crónica al cadmio. Los experimentos se realizaron con ratas Wistar (200g), incluidas en tres grupos experimentales: 1) ratas a las que se administró cadmio (1,2 mg/kg/día, s.c.) cinco veces por semana, durante nueve semanas, 2) ratas a las cuales se les administró quercetina (50 mg/kg/día, i.p.) cinco veces por semana, empezando en la cuarta semana y 3) ratas a las que se administró cadmio y quercetina. La lesión renal se evaluó midiendo proteinuria, microalbuminuria y glucosuria, así como la excreción de enzimas urinarias N-acetil-beta-D-glucosaminidasa, fosfatasa alcalina y gamma-glutamil-transpeptidasa. Las muestras de plasma se utilizaron para la determinación de creatinina y nitrógeno ureico plasmático, así como dialdehido malónico, como índice de peroxidación lipídica y antioxidantes totales en plasma. En riñón se midió la actividad enzimática de la superóxido dismutasa y de la glutation reductasa. Nuestros resultados mostraron que la administración de cadmio durante 9 semanas produjo un incremento en los valores de flujo urinario, proteinuria, microalbuminuria y glucosuria. El tratamiento con cadmio incluso incrementó la creatinina sérica y el nitrógeno uréico plasmático y elevó drásticamente la actividad de enzimas urinarias. Finalmente el aclaramiento de creatinina disminuyó como consecuencia de la disfunción renal. La administración de quercetina con cadmio mostró una clara mejora en la función renal y revirtió dichas alteraciones. La peroxidación lipídica se incrementó en las ratas tratadas con cadmio y este incremento fue revertido por la administración de quercetina. La concentración de antioxidantes totales en plasma, fue más alta en el grupo que recibió cadmio y quercetina. El grupo tratado con cadmio mostró una disminución en la actividad de la superóxido dismutasa y la glutation reductasa en riñón, sin embargo en el grupo al que se administró también quercetina este descenso fue significativamente menor. Este estudio revela que la quercetina tiene un efecto protector frente a la nefrotoxicidad producida por cadmio y que su propiedad antioxidante parece ser la responsable de esta acción protectora (AU)

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