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PubMed2000

Impact of uremia on female reproductive cyclicity, ovulation, and luteinizing hormone in the rat.

BACKGROUND: Impaired reproductive function accompanies chronic renal insufficiency (uremia) in both the human and experimental animal. Clinical hypogonadism occurs in both genders. The present studies were designed to investigate possible anti-ovulatory effects of uremia in the female rat, a species that produces multiple ova during the normal estrous cycle. METHODS: Renal insufficiency (uremia) was induced by 5/6 nephrectomy. Two control groups comprised sham-operated animals fed ad libitum (sham) or pair-wise with the uremic animals (pair-fed). Estrous cycles were determined by cytology of vaginal lavage. We examined concomitant changes in the preovulatory luteinizing hormone (LH) surge by radioimmunoassay (RIA), immunoradiometric assay (IRMA), and bioassay. Repetitive LH measurements were made from blood samples taken by intra-atrial catheter throughout the afternoon and evening of proestrus. The following morning (estrus), ovaries were collected, and ova were enumerated per oviduct. RESULTS: Experimentally uremic animals manifested a threefold elevation of plasma creatinine and urea nitrogen and concomitantly a more than 50% impoverishment of ova production. Analyses of a large group of animals (N = 83) by RIA revealed uremia-associated attenuation of the preovulatory LH surge. Further measurements of the preovulatory LH surge by independent IRMA and LH bioassay (N = 26) corroborated this attenuation. Additional experiments indicated that these hormonal changes, but not changes in ovulation, might further reflect modulation of LH release by the anesthesia used in the preparative nephrectomy and catheterization surgeries. When normalized to body weight, the ovaries of uremic rats were found to weigh more than those of either the sham or pair-fed animals. CONCLUSIONS: The present experiments take advantage of an experimental uremic model to document a consistent decrease in the number of ova released during estrus in the uremic animal. Possible disruption of hypothalamic-pituitary-ovarian regulation is further highlighted by attenuation in the preovulatory LH surge. These results provide a basis for further studies of neuroendocrine pathophysiology in a rodent model of uremia-associated ovulatory disruption.

Amenorrhea↗
PubMed2003

Calpain is a mediator of myocardial injury in experimental uremia: is it activated by endogenous ouabain?

BACKGROUND: Incidence of cardiovascular disease is more than 20-fold higher in patients with chronic renal failure than in aged-matched individuals with normal renal function. Little is understood about the causes or the mechanism of uremia-induced cardiovascular injury, but the involvement of calpain as a possible mediator has recently been under investigation. Mean calpain activity was found to be 3.4-fold higher in the hearts of uremic rats than in control or spontaneously hypertensive (SHR) rats. In addition, calpain activity was found to be stimulated in myoblasts (Girardi) treated with media enriched with uremic serum compared with cells treated with serum from healthy volunteers. In this study, we assessed the impact of calpain activation in uremia and explored the possibility that calpain might be activated in uremia by endogenous ouabain. Ouabain is known to be elevated in uremia and is strongly associated with left ventricular hypertrophy in essential hypertension. METHODS: Calpain activity was measured in situ in human-derived myoblasts treated with low doses of ouabain similar to those concentrations found in uremic patients. RESULTS: Low concentrations of ouabain (10 nmol/L) caused a highly significant increase in calpain activity, which could be completely inhibited by the simultaneous chelation of intracellular and extracellular Ca2+, and by the chelation of extracellular Ca2+ alone. CONCLUSIONS: Calpain activity can be stimulated by nanomolar concentrations of ouabain due to an influx of extracellular Ca2+. As circulating ouabain is known to be elevated in uremia and strongly associated with LVH remodeling, we hypothesize that endogenous ouabain might be one of the factors that facilitates the remodeling of the left ventricle in patients with renal failure.

Calpain↗
PubMed1975

Increased cardiac contractility in acute uremia: interrelationships with hypertension.

To study the effects of acute uremia on the inotropic state of the rat heart, we subjected rats to bilateral nephrectomy and studied their hearts in the open chest 24 h later. Uremic rats had significantly higher systolic blood pressure than sham-operated animals. Left ventricular systolic pressure and maximum dP/dt, both during ejection and isovolumic contrations, were higher for any given end-diastolic pressure in hearts of uremic rats than in sham-operated animals. This difference in performance charcteristics was not abolished by doses of propranolol that blocked the heart rate response to isoproterenol. The administration of phenoxybenzamine during the 24 h of uremia abolished the blood pressure rise in uremic rats, but the increased contractile state persisted. Treatment of sham-operated animals with methoxamine to produce the same course of blood pressure as observed in uremic rats was also associated with an increased inotropic state. These results indicate that in the rat, acute uremia is associated with an increased inotropic state that is not mediated by beta-adrenergic mechanisms. The systolic hypertension of acute uremia is not the major cause of the increased contractility, although systolic hypertension without uremia can mimic the performance characteristics found in hearts of uremic rats.

Animals↗
PubMed1984

Role of uremia, brain calcium, and parathyroid hormone on changes in electroencephalogram in chronic renal failure.

Acute uremia is associated with increased calcium (Ca) in brain and changes in electroencephalogram (EEG), and both derangements are related to excess parathyroid hormone (PTH). Also changes in EEG in patients with chronic renal failure (CRF) correlated directly with blood levels of PTH, and fall in PTH was followed by improvement in EEG. We examined whether chronic uremia per se has an effect on brain calcium or EEG. Uremia was produced by 5/6 nephrectomy and maintained for 32-70 wk in seven thyroparathyroidectomized (TPTX) and seven control dogs. There were no differences in creatinine clearance and serum electrolytes except for HCO3, which was lower in control animals (P less than 0.01). Serum PTH was undetectable in TPTX dogs but was significantly elevated in control animals (32.3 +/- 3.3 mu leq /ml). Calcium in gray and white matter was significantly increased in both groups but much higher in control animals. The percent waves of less than 7 Hz in EEG were similar in both groups prior to uremia (TPTX 4.6 +/- 0.8 vs. control 4.2 +/- 0.5%) but remained unchanged in TPTX animals and increased significantly in control dogs (19.0 +/- 1.3%) after uremia. These data suggest that CRF per se is associated with marked rise in Ca in both gray and white matter and increment is higher in the presence of PTH. Disturbance in EEG in a state of CRF requires the presence of excess PTH and is prevented despite increased Ca in brain if hyperparathyroidism is not allowed to develop.

Animals↗
PubMed1980

Urea synthesis by perfused rat liver in experimental uremia.

Urea synthesis was examined in experimental uremia using the isolated perfused rat liver in order to assure strict control of substrate (NH4Cl) presented to the liver. Acute uremia was created in female Sprague-Dawley rats by bilateral nephrectomy (n = 7) 48 h prior to studies. Chronic uremia (8--14 weeks) was produced by right nephrectomy and segmental infarction of the left kidney in 7 rats. At infusion rates of NH4Cl (8.3 mumol/min) which resulted in prehepatic perfusate ammonia levels approximately twice the previously described Km value, livers of chronically uremic rats had slightly higher rates of urea production than controls (controls: 0.41 +/- 0.03; chronic uremia: 0.54 +/- 0.04 mumol/min/g of wet liver weight; p less than 0.02). In acute uremia, urea production was higher (0.66 +/- 0.05 mumol/min/g) than in sham-operated rats (0.59 +/- 0.05 mumol/min/g) but the differences did not achieve statistical significance. Simultaneously performed taurocholate transport studies did not reveal significant functional differences between the livers of uremic and control animals. The data suggest that urea production by livers of uremic rats is increased when compared to that of control animals.

Acute Disease↗
PubMed1983

Insulin resistance in uremia. Characterization of lipid metabolism in freshly isolated and primary cultures of hepatocytes from chronic uremic rats.

UNLABELLED: We have studied the mechanism(s) of hyperlipidemia and liver insulin sensitivity in a rat model of severe chronic uremia (U). Basal lipid synthesis was decreased in freshly isolated hepatocytes from U when compared with sham-operated ad lib.-fed controls (alfC). Basal lipid synthesis in pair-fed controls (pfC) was in between U and alfC. Similarly, the activity of liver acetyl CoA carboxylase, fatty acid synthetase, citrate cleavage enzyme, malate dehydrogenase, and glucose-6-phosphate dehydrogenase was diminished in U. Muscle and adipose tissue lipoprotein lipase was also decreased. Insulin stimulated lipid synthesis in freshly isolated hepatocytes from alfC. Hepatocytes from U and pfC were resistant to this effect of insulin. To ascertain if the insulin resistance in U was due to starvation (chow intake 50% of alfC) or to uremia itself, the U and pfC were intragastrically fed an isocaloric diet via a Holter pump the last week of the experimental period. Hepatocytes from orally fed U and pfC were also cultured for 24 h in serum-free medium. While freshly isolated and cultured U hepatocytes remained insulin resistant, those from pfC normalized, in vivo and in vitro, when they were provided with enough nutrients. CONCLUSIONS: (a) Hyperlipidemia in uremia is not due to increased synthesis, but to defect(s) in clearance. (b) Insulin does not stimulate lipid synthesis in uremia. This finding, along with our recent demonstration that insulin binding and internalization are not decreased in the uremic liver, suggests that a post-binding defect(s) in the liver plays an important role in the mechanism(s) of insulin resistance in uremia. (c) Cultured hepatocytes from uremic rats remain insulin resistant. This quality renders these cells useful in studying the postinsulin binding events responsible for the insulin-resistant state in the absence of complicating hormonal and substrate changes that occur in vivo.

Animals↗
PubMed1984

Glucagon-stimulable adenylyl cyclase in rat liver. Effects of chronic uremia and intermittent glucagon administration.

The effects of chronic uremia and glucagon administration on glucagon-stimulable adenylyl cyclase in rat liver were assessed by determinations of adenylyl cyclase activities, specific iodoglucagon binding, and the activity of the stimulatory regulatory component of adenylyl cyclase. Glucagon-stimulated adenylyl cyclase was reduced in uremia to 75-80% of control levels (P less than 0.05), in the presence or absence of saturating levels of guanosine triphosphate (GTP) and 5'-guanylylimidodiphosphate [GMP-P(NH)P]. Although these changes were accompanied by a concomitant 20% reduction in sodium fluoride-stimulated activity, basal, GTP-, GMP-P(NH)P-, and manganese-dependent adenylyl cyclase activities were unchanged. Using [125I-Tyr10]monoiodoglucagon as a receptor probe, the number of high affinity glucagon-binding sites was reduced 28% (P less than 0.01) in uremic as compared with control liver membranes. However, the affinity of these binding sites was unaltered. The S49 cyc- -reconstituting activity with respect to both GMP-P(NH)P- and isoproterenol plus GTP-stimulable adenylyl cyclase was unaltered in membranes from uremic as compared with control rats. Intermittent glucagon (80-100 micrograms) injections administered at 8-h intervals to normal rats reproduced all of the above described effects of chronic experimental uremia on the adenylyl cyclase system. It is concluded that changes in the hormone-stimulable adenylyl cyclase complex in uremia and with glucagon treatment result primarily from a decrease in the number of hormone-specific receptor sites in hepatic plasma membranes. Since the changes in liver adenylyl cyclase are qualitatively and quantitatively the same in glucagon-treated and uremic rats, it is suggested that these may be the result of the hyperglucagonemia of uremia. Further, the data reveal an unexpected dissociation between guanine nucleotide and sodium fluoride stimulation of adenylyl cyclase. Possible causes for this dissociation based on the known subunit composition of cyclase coupling proteins are discussed.

Adenylyl Cyclases↗
PubMed2005

Role of leptin and melanocortin signaling in uremia-associated cachexia.

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

Agouti-Related Protein↗
PubMed2001

Chronic uremia induces permeability changes, increased nitric oxide synthase expression, and structural modifications in the peritoneum.

Advanced glycation end products (AGE), growth factors, and nitric oxide contribute to alterations of the peritoneum during peritoneal dialysis (PD). These mediators are also involved in chronic uremia, a condition associated with increased permeability of serosal membranes. It is unknown whether chronic uremia per se modifies the peritoneum before PD initiation. A rat model of subtotal nephrectomy was used to measure peritoneal permeability after 3, 6, and 9 wk, in parallel with peritoneal nitric oxide synthase (NOS) isoform expression and activity and structural changes. Uremic rats were characterized by a higher peritoneal permeability for small solutes and an increased NOS activity due to the up-regulation of endothelial and neuronal NOS. The permeability changes and increased NOS activities correlated with the degree of renal failure. Focal areas of vascular proliferation and fibrosis were detected in uremic rats, in relation with a transient up-regulation of vascular endothelial growth factor and basic fibroblast growth factor, as well as vascular deposits of the AGE carboxymethyllysine and pentosidine. Correction of anemia with erythropoietin did not prevent the permeability or structural changes in uremic rats. Thus, in this rat model, uremia induces permeability and structural changes in the peritoneum, in parallel with AGE deposits and up-regulation of specific NOS isoforms and growth factors. These data suggest an independent contribution of uremia in the peritoneal changes during PD and offer a paradigm to better understand the modifications of serosal membranes in uremia.

Anemia↗
PubMed1992

Impaired atrial natriuretic factor systemic clearance contributes to its higher levels in uremia.

To evaluate the interaction between plasma levels and the systemic uptake of atrial natriuretic factor (ANF) with thyroid hormone levels during acute renal failure (ARF), seven groups of rats were analyzed: Group 1, Controls (C); Group 2, ARF; Group 3, filtering kidney with uremia; Group 4, ARF with thyroxine (T4) supplement (ARF + T4); Group 5, thyroidectomy (Tx); Group 6, ARF on Tx rats (Tx + ARF); Group 7, Tx + ARF supplemented with T4 (Tx + ARF + T4). Plasma creatinine (Cr), urea, T4, blood volume, and ANF were measured; ANF half-life (ANF t1/2; expressed in seconds) was calculated. Rats with ARF developed uremia (Cr, 377 +/- 58 versus 41 +/- 5 mumol/L), significant reduction in T4 (40 +/- 4 versus 89.2 +/- 6 nmol/L). elevation of ANF (287.7 +/- 35 versus 60.9 +/- 8 fmol/mL), and lengthening of ANF t1/2 (69.7 +/- 8 versus 37.2 +/- 6 s) compared with C (P less than 0.01). T4 supplements to ARF rats resulted in a lesser degree of uremia (Cr, 283 +/- 27; P less than 0.05) and normalization of ANF t1/2 (31.4 +/- 5); however, ANF levels remained higher than C (100.4 +/- 11.4 versus 60.9 +/- 8; P less than 0.01). Tx by itself did not change either parameter. The filtering kidney with uremia group developed mild uremia (Cr, 199 +/- 8), T4 fell (58 +/- 8), ANF levels rose (83.4 +/- 5.4), and ANF t1/2 was prolonged (54.5 +/- 12). Tx before ARF doubled the ANF level and lengthened ANF t1/2 similarly than in ARF. T4 addition (Tx + ARF + T4) normalized ANF t1/2 (29.8 +/- 3) in spite of a persistently high ANF (145.7 +/- 21). Blood volume did not change in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

The effect of uremia on penicillin flux between blood and cerebrospinal fluid.

The effect of uremia on the choroid plexus system responsible for transport of penicillin from cerebrospinal fluid (CSF) to blood was studied in vitro and in vivo. Uremia was induced in rabbits by injecting toxic doses of cephaloridine or by obstructing urine flow. Three days after the induction of uremia, isolated choroid plexuses from normal rabbits were unable to concentrate penicillin 14C normally when incubated in either CSF or ultrafiltrates of plasma from uremic rabbits. In vivo, a decrease in the disappearance of penicillin 14C from CSF was observed in uremic rabbits. However, the choroid plexus transport system for penicillin was only partially and reversibly depressed in uremia. The increased CSF levels of penicillin uremia are due to: decreased excretion of penicillin by the kidney, depression of active efflux of penicillin from the CSF, and decreased plasma binding of penicillin.

Animals↗
PubMed1987

Acute uremia following dietary potassium depletion. II. Effect on tissue carbohydrate composition.

In order to evaluate the potential role of hyperkalemia and metabolic acidosis on the disturbances of carbohydrate metabolism normally seen in uremia, a specific model of acute uremia devoid of hyperkalemia and severe metabolic acidosis was chosen. Therefore, rats were deprived of potassium prior to induction of acute uremia. Potassium depletion caused a significant decrease of muscle and liver glycogen due to activation of phosphorylase kinase, whereas glycogen concentration in heart muscle was unchanged and elevated in the kidney of sham-operated and ureter-ligated animals. In contrast, glucose concentrations were enhanced in the liver and the kidney, unchanged in heart muscle and decreased in skeletal muscle. We conclude that carbohydrate abnormalities occur in acute uremia despite normokalemia and mild metabolic acidosis. Furthermore, acute uremia accompanied by prior potassium depletion results in no net effect on cardiac glycogen metabolism but stimulates glycogenolysis in both skeletal muscle and the liver.

Animals↗
PubMed1982

Prostacyclin and thromboxane in chronic uremia: effect of hemodialysis.

To study the effects of uremia and hemodialysis on the production rates of antiaggregatory prostacyclin (PGI2) and proaggregatory thromboxane A2 (TxA2), we collected serial plasma samples from eight patients with chronic uremia before, during and after hemodialysis and assayed them for 6-keto-PGF1 alpha and TxB2, the stable metabolites of PGI2 and TxA2, respectively. In addition, the capacity of the platelets to produce TxB2 during spontaneous clotting was studied by measuring the TxB2 levels in serum incubated at +37 degrees C for 60 minutes. The PGI2 production of the uremia patients before hemodialysis was less (P less than 0.001) than that of healthy volunteers. It rose significantly following heparinization and remained elevated during hemodialysis. TxB2 generation by platelets during clotting was diminished in uremia. Plasma TxB2 levels were normal before, but increased during hemodialysis. Thus, profound changes in the PGI2/TxA2-system seem to be associated with uremia and hemodialysis.

6-Ketoprostaglandin F1 alpha↗
PubMed1980

Nitrogen metabolism and growth in experimental uremia.

Growth in length, weight gain and gain of body nitrogen were compared in rats with stable long-term uremia (U) resulting from subtotal two-stage nephrectomy with irradiation of residual parenchyma, in sham-operated pair-fed control rats (PFC) and in ad libitum fed control rats (LC). Growth in length and weight gain were considerably lower in U than in LC rats, reflecting mainly diminished intake of food in uremia. However, they were also significantly lower in U than in PFC despite identical intake of food, pointing to a specific adverse effect of uremia on growth. Whole body dry matter, whole body nitrogen and weight of a reference muscle (triceps surae) were significantly lower in U than in PFC animals, showing that dietary nitrogen and/or energy are less efficiently utilized for protein synthesis in U animals. Diminished net nitrogen retention was paralleled by increased urinary nitrogen loss (excretion of urea, alpha-amino nitrogen, protein, and creatinine). Within the precision of the method used, no significant difference of oxygen consumption between U and PFC animals could be demonstrated. The plasma amino acid pattern was deranged and the tyrosine/phenylalanine ratio was decreased despite no change in hepatic phenylalanine hydroxylase. The findings document increased nitrogen and/or energy cost of growth in rats with stable chronic uremia; this finding agrees with previous observations of disturbed protein metabolism and hypercatabolism in experimental uremia.

Amino Acids↗
PubMed1977

Effect of acute uremia on arginine metabolism and urea and guanidino acid production by perfused rat liver.

Since arginine is a precursor of urea and other guanidino derivatives, we have evaluated its metabolism in acute uremia using the isolated perfused rat liver. Female Sprague-Dawley rats underwent bilateral nephrectomy (n = 5) or sham operation (n = 5) 48 h prior to liver perfusion. Fifty microCi of L-[guanidino 14C] arginine and unlabelled arginine and aspartic acid were added to the recycling perfusate 15 min prior to liver perfusion. Perfusate concentrations of urea and other guanidino derivatives were measured with high-pressure liquid chromatography. After the initial 30 min of perfusion, net uptake of arginine was lower, and net release of guanidino-succinic acid (GSA) was higher in the livers of acutely uremic rats. Net release of urea was also higher in uremia but the results did not achieve statistical significance. In uremia, the percent conversion of 14C arginine to 14C urea was significantly higher (79 +/- 5 [SE]%) than in controls (58 +/- 7%). These results demonstrate increased GSA production by livers of acutely uremic rats and suggest that acute uremia may be associated with increased arginine utilization and increased production of urea.

Acute Kidney Injury↗
PubMed1986

The influence of uremia and immunosuppression on an animal model for ischemic colitis.

Up to 1 percent of renal transplant recipients have been reported to develop ischemic colitis. Immunosuppressive agents and uremia have been implicated in the development of this complication, but their exact relationship remains unclear. A rat model was developed to determine the effects of uremia alone and in combination with immunosuppression on the development of ischemic colitis. Seventy-six animals were included in the study. Uremia and ischemic colitis were induced surgically. The immunosuppressive agents azathioprine and methylprednisolone were administered for 72 hours after a colonic segment was devascularized in chronically uremic rats. One-way analysis of variance (ANOVA) showed that uremia potentiates colonic ischemia significantly (4.09 cm2 vs 1.25 cm2, P less than 0.03). The addition of parenteral steroids (methylprednisolone) or azathioprine alone and in combination did not potentiate or reduce this ischemic process in uremic animals. Each of these factors alone is commonly present in the renal transplant population and can contribute to the development of potentially fatal ischemic colitis.

Animals↗
PubMed2005

Analysis of proteomic components of sera from patients with uremia by two dimensional electrophoresis and matrix assisted laser desorption/ ionization time of flight mass spectrometry.

The different sera proteomic components between uremia patients and normal subjects were studied through two-dimensional gel electrophoresis technique. Immobilized pH gradient two-dimensional polyacrylamide gel electrophoresis (2DE), silver staining, ImageMaster 2D 5.0 analysis software, matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-TOF-MS) and IPI human database searching were used to separate and identify the proteome of the sera from the patients with uremia. The results showed that satisfactory 2DE patterns of the serum proteins were obtained. Twenty-six protein spots showed significant difference in quantity in uremia patients, and 20 protein spots were identified by MALDI-TOF-TOF-MS. It was concluded that good reproducibility could be obtained by applying immobilized pH gradient 2DE to separate and identify the proteome in serum, which provided the foundation for the further study on uremia toxins pertaining to protein.

Adult↗
PubMed1986

Effect of chronic uremia on the cardiovascular alpha 1 receptor.

Adrenergic dysfunction in uremia has been well described. Several lines of evidence suggest disorders of blood pressure regulation and myocardial response may occur secondary to adrenergic dysfunction; attenuated pressor response to norepinephrine (NE) in uremia; attenuated chronotropic responses during dialysis induced hypotension. Since the adrenergic receptors are the effector component of the adrenergic nervous system, we have employed the partially nephrectomized uremic rat, to examine the effect of chronic uremia (4-6 weeks) on the binding properties of alpha 1 receptors in rat mesenteric artery and myocardial tissue. The results indicate that moderate levels of uremia alter the binding properties of both the alpha 1 vascular and myocardial receptor.

Animals↗