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.

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)

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.

La transición de células epiteliales a miofibroblastos. Mecanismos involucrados y su posible relación con la fibrosis renal / No disponible

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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.

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)

Temporal changes in renal endoglin and TGF-alfa1 expression following ureteral obstruction in rats

Chronic renal disease is characterized by the accumulation of extracellular matrixproteins in the kidney and a loss of renal function. Tubulointerstitial fibrosis hasbeen reported to play an important role in the progression of chronic renal diseases.Transforming growth factor-beta1 (TGF-alpha1) is a profibrotic cytokine playing amajor contribution to fibrotic kidney disease. Endoglin is a membrane glycoproteinof the TGF-alpha1 receptor system. The aim of this work was to determine the timecourseexpression of renal type I and IV collagens, endoglin and TGF-alpha1 in a ratmodel of induced tubulointerstitial fibrosis at 1, 3, 10 and 17 days after unilateralureteral obstruction (UUO). In 17 days-ligated (L)-renal samples, a marked interstitialfibrosis was detected by Masson’s trichromic and Sirius red staining, accompaniedby an increase in type I collagen expression as shown by immunohistochemicalanalysis. Northern blot studies revealed a progressive increase in collagen alpha2(I),TGF-alpha1 and endoglin mRNA expression in L kidneys when compared with the correspondingnon-ligated (NL) kidneys from the animals subjected to left UUO. Seventeendays after UUO, significant increases in collagen alpha2(I), collagen alpha1(IV),TGF-alpha1 and endoglin mRNA levels were detected in L kidneys vs NL kidneys. Significantlyhigher levels of the protein endoglin were found in L kidneys than in NLkidneys 10 and 17 days following obstruction. A marked increase expression forendoglin and TGF-alpha1 was localized in renal interstitium by immunohistochemical studies 17 days after obstruction. In conclusion, this work reports the upregulationof endoglin coincident to that of its ligand TGF-alpha1 in the kidneys of rats with progressivetubulointerstitial fibrosis induced by UUO (AU)

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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.

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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El TGF-beta síntesis y mecanismo de acción / TGF-ß: synthesis and mecanism of action

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Effect of chronic and progressive aortic constriction on renal function and structure in rats.

The purpose of this study was to evaluate the functional and structural renal damage observed in aortic-constricted hypertensive rats and to identify their possible relationship with transforming growth factor beta (TGF-beta) expression. Progressive renovascular hypertension was induced by progressive aortic constriction between the two renal arteries. Three months after constriction, the glomerular filtration rate (GFR), effective renal blood flow (ERBF), perfusion pressure (PP), urinary protein excretion (UPE) and urinary electrolyte excretion (U(Na)V and U(K)V) in the kidney above (right kidney, RK) and below the ligature (left kidney, LK) were measured. The cross-sectional corpuscular, capillary tuft and mesangial matrix area and tubulo-interstitial fibrosis were measured in tissue sections stained with Syrius Red using a computer-assisted image analysis system. TGF-beta was detected by immunohistochemistry. The functional parameters were similar in the two kidneys of aortic-constricted hypertensive rats (GFR-RK, 1.33+/-0.08 vs. LK, 1.18+/-0.08 mL/min; ERBF-RK, 9.23+/-1.32 vs. LK, 8.18+/-0.91 mL/min; RVR-RK, 28.3+/-3.9 vs. LK, 21.7+/-3.2 mmHg x min/mL). The RK was subject to a higher PP than the LK (176+/-7 vs. 128+/-5 mmHg, P < 0.05). UPE, U(Na)V, and U(K)V were greater in the RK than in the LK (UPE-RK, 512+/-61 vs. LK, 361+/-38 microg/30 min, P < 0.05; U(Na)V-RK, 0.056+/-0.012 vs. LK, 0.022+/-0.006 mEq/30 min, P < 0.05; UKV-RK, 0.042+/-0.006 vs. LK, 0.029+/-0.003 mEq/30 min, P < 0.05). Morphometric analysis revealed that the RK capillary tuft area and mesangial matrix area were higher than those in the LK. The LK had a higher degree of interstitial fibrosis than the RK. No significant differences in TGF-beta immunostaining were observed between the RK and the LK. In conclusion, the RK (subjected to hypertension) of aortic-constricted hypertensive animals developed glomerular fibrosis, only in the outer glomeruli whereas the LK developed mild interstitial fibrosis. Neither glomerular nor interstitial fibrosis seem to be responsible for the proteinuria observed in both kidneys.

Vascular gene transfer driven by endoglin and ICAM-2 endothelial-specific promoters.

The involvement of the vascular endothelium in a large number of diseases supports the importance of vascular-specific gene delivery for their treatment. The hereditary hemorrhagic telangiectasia type 1 is an example of a vascular inherited disease (OMIM 187300). This is an autosomal dominant vascular disorder originated by mutations in the endoglin gene and associated with frequent epistaxis, telangiectases, gastrointestinal bleedings, and arteriovenous malformations in brain, lung and liver. Here, we address for the first time the possibility of using in vivo gene transfer to target endoglin expression to the vasculature. The promoter of the endothelial gene, ICAM-2, was used to generate transgenic animals which demonstrated endothelial expression of endoglin. Next, the promoters of the human endothelial genes, endoglin and ICAM-2, were inserted upstream of the human endoglin cDNA, and the resulting constructs were systemically or locally delivered, demonstrating endoglin expression in the vessel walls of liver, lung and skin. These gene transfer experiments represent an initial step in the treatment of the hereditary hemorrhagic telangiectasia type 1 by gene therapy, and suggest that endoglin and ICAM-2 promoters can be used to deliver other genes to the endothelium specifically.

Up-regulation of endoglin, a TGF-beta-binding protein, in rats with experimental renal fibrosis induced by renal mass reduction.

BACKGROUND: The central process in chronic renal failure is the progressive accumulation of extracellular matrix in the glomeruli and in the tubulo-interstitial space, resulting in renal fibrosis. Transforming growth factor-beta1 (TGF-beta1) up-regulation plays a major role in the genesis of renal fibrosis. Endoglin is a membrane glycoprotein that binds TGF-beta1 and TGF-beta3 with high affinity. An increased level of endoglin immunostaining has been demonstrated previously in biopsies from patients with chronic progressive renal disease. We have assessed the expression of endoglin in the rat 5/6th renal mass reduction (RMR) model. METHODS: One, 3 and 5 months after RMR, mean arterial pressure and renal function were measured, animals were sacrificed, renal fibrosis was evaluated quantitatively and the expression of endoglin was assessed by western blot, northern blot and immunohistochemistry. RESULTS: RMR induced a progressive increase in mean arterial pressure and urinary protein excretion. Renal corpuscular area, and mesangial and interstitial fibrosis increased with time after RMR. Immunohistochemical staining for endoglin demonstrated its expression mainly on the endothelial surface of major vessels. In kidneys 1 and 3 months after RMR, the expression of endoglin in renal corpuscles was limited to Bowman's parietal epithelium. In rats 5 months after RMR, the immunoexpression in glomerular endothelium was more marked. Northern blot analysis revealed that rats with RMR showed an increase in the expression of mRNA for endoglin, only at 5 months after RMR. Western blot analysis gave a different time course: a marked increase in the first month, a decrease in the 3rd month and a further increase in the 5th month after RMR. CONCLUSIONS: The present study demonstrates increased endoglin expression in rats with severe hypertension and renal damage. This increased endoglin expression coincides with the period of higher renal damage and renal dysfunction.

Renal fibrosis in diabetic and aortic-constricted hypertensive rats.

To assess if the renal damage observed in rats with diabetes and hypertension is due to hemodynamic or metabolic changes, a progressive aortic constriction between the two renal arteries has been done in streptozotocin-induced diabetic rats (constriction + diabetes group) and in nondiabetic rats (constriction group). This model allows us to study two kidneys subjected to different perfusion pressure (PP) in the same metabolic environment. One-month-old rats (100-120 g body wt) were subjected to the aortic constriction procedure. Three months after constriction, glomerular filtration rate and renal plasma flow were similar in both kidneys of the two groups. PP was greater in the kidney placed over the ligature [constriction high-pressure kidney (CH) or constriction + diabetic high-pressure kidney (DH)] than in the one placed below the ligature [constriction low pressure (CL) or constriction + diabetic low pressure (DL)]. Proteinuria was higher in the CH than in the CL kidneys (512 +/- 61 vs. 361 +/- 38 microg/30 min, respectively) and much higher in the DH kidney (770 +/- 106 microg/30 min). Renal fibrosis was measured in tissue sections stained with Syrius red using a computer-assisted image analysis system. DH and DL kidneys showed higher corpuscular cross-sectional and capillary tuft areas than the CH and CL ones. The DH kidney showed slight mesangial expansion and thickening of the capillary walls, which were more pronounced in the former. Most renal corpuscles from CH and DH groups were nearly normal in morphology appearance, and only in some instances a slight increment in mesangium was observed. Transforming growth factor-beta1 (TGF-beta1) immunostaining revealed that DH kidneys showed the highest glomerular expression. We concluded that 1) diabetic animals develop glomerular but not interstitial fibrosis to a greater extent than nondiabetic animals and that this lesion principally occurs in the hypertensive kidney (DH), and 2) increased TGF-beta expression is associated with diabetic renal damage.

Renal ischemia in the rat stimulates glomerular nitric oxide synthesis.

Renal ischemia in humans and in experimental animals is associated with a complex and possibly interrelated series of events. In this study, we have investigated the glomerular nitric oxide (NO) production after renal ischemia. Unilateral or bilateral renal ischemia was induced in Wistar rats by clamping one or both renal arteries. NO production was assessed by measuring glomerular production of nitrite, a stable end product of NO catabolism, and NO-dependent glomerular cGMP production and by assessing the glomerular NADPH diaphorase (ND) activity, an enzymatic activity that colocalizes with NO-synthesis activity. Furthermore, we determined the isoform of NO synthase (NOS) implicated in NO synthesis by Western blot and immunohistochemistry. Glomeruli from rats with bilateral ischemia showed elevated glomerular nitrite and cGMP production. Besides, glomeruli from this group of rats showed an increased ND activity, whereas glomeruli from the ischemic and nonischemic rats with unilateral ischemia did not show this increase in nitrite, cGMP, and ND activity. In addition, glomeruli from ischemic kidneys showed an increased expression of endothelial NOS without changes in the inducible isoform. Addition of L-NAME in the drinking water induced a higher increase in the severity of the functional and structural damage in rats with bilateral ischemia than in rats with unilateral ischemia and in sham-operated animals. We can conclude that after renal ischemia, there is an increased glomerular NO synthesis subsequent to an activation of endothelial NOS that plays a protective role in the renal damage induced by ischemia and reperfusion.

Mecanismos implicados en la nefrotoxicidad producida por aminoglucósidos / Pathogenic factors in aminoglycoside-induced nephrotoxicity

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Role of glomerular nitric oxide in glycerol-induced acute renal failure.

Myoglobinuric acute renal failure remains one of the least understood clinical syndromes and the mediators involved remain obscure. The aim of the present study was to assess the role of nitric oxide in glycerol-induced acute renal failure under normal conditions and after uninephrectomy. Acute renal failure was induced in rats by injection of 50% glycerol (10 mL x kg(-1) body weight). Half of the animals were subjected to uninephrectomy two days before glycerol injection. Two days after the induction of acute renal failure, glomeruli from some animals were isolated and glomerular nitrite production was measured. Another group of animals was used for acute clearance studies. In this case, the effect of infusing either L-NAME or L-arginine was assayed. Glomerular nitrite production was significantly decreased in glycerol-induced acute renal failure. Glomeruli from uninephrectomized animals showed an increase in nitrite production, both in normal conditions and after glycerol injection, as compared with glomeruli from non-nephrectomized animals. L-NAME infusion worsened renal function in all the study groups, but more slowly in animals with glycerol-induced acute renal failure than in control rats. In uninephrectomized animals L-NAME reduced renal function more than in animals with two kidneys. In conclusion, in this model of acute renal failure the decrease in glomerular nitric oxide production plays an important role in the decrease in renal function. After uninephrectomy, an increase in glomerular nitric oxide synthesis plays a protective role against glycerol-induced acute renal failure.