Renal Arteriovenous Difference Research Articles

Effects of the SGLT2 inhibitor ipragliflozin on food intake, appetite-regulating hormones, and arteriovenous differences in postprandial glucose levels in type 2 diabetic rats.

The sodium-glucose cotransporter (SGLT) 2 inhibitor, ipragliflozin, improves not only hyperglycemia but also obesity in type 2 diabetic animals and patients; however, there have been concerns that it may also cause an increase in compensatory food intake. Appetite is regulated by complex mechanisms involving the central nervous system, part of which involves appetite-related hormones and arteriovenous differences in postprandial glucose levels. We evaluated the effect of ipragliflozin in type 2 diabetic rats on food intake, appetite-related hormones and arteriovenous differences in postprandial glucose levels, and their correlation with food intake. Ipragliflozin and several antidiabetic drugs were administered to type 2 diabetic rats and various parameters concerning food intake were measured. Ipragliflozin significantly increased urinary glucose excretion and reduced postprandial hyperglycemia. Compared to normal rats, diabetic rats exhibited hyperphagia and elevated plasma levels of the appetite-stimulating hormones neuropeptide Y and ghrelin. Ipragliflozin induced significant weight loss and reduced plasma levels of appetite-stimulating hormones without affecting food intake. Diabetic rats exhibited a significantly reduced arteriovenous difference in postprandial glucose levels due to insulin insufficiency; this was improved by ipragliflozin, which increased renal arteriovenous differences in glucose levels by increasing urinary glucose excretion. These results indicate that the SGLT2 inhibitor, ipragliflozin, exerts antihyperglycemic actions by increasing urinary glucose excretion, and induces weight loss without a compensatory increase in food intake in type 2 diabetic mice. The mechanisms underlying these effects can be attributed, in part, to an increased arteriovenous difference in postprandial glucose levels and improved regulation of appetite-related hormones in the diabetic animal model. While this study was conducted in rodents and the results may be distinct from those in humans, it is possible that some of the pharmacological mechanisms, including the regulation of appetite-related hormones, can be extrapolated to clinical settings and may be valuable for further studies including clinical investigations.

Contribution of the Renal Medulla to Enhanced Ketogenesis with Ringer's Acetate Administration during Hepatic Inflow Occlusion RID="" ID="" This International Society of Surgery (ISS)/Société Internationale de Chirurgie (SIC) article was presented at the 37th World Congress of Surgery International Surgical Week (ISW97), Acapulco, Mexico, August 24–30, 1997.

We have reported that the administration of Ringer's acetate solution (AR) maintains plasma ketone body concentrations even during hepatic ischemia due to enhanced ketogenesis in the kidney. In this study we tried to clarify which part of the kidney, cortex or medulla, contributes to the enhanced ketogenesis. During 20 minutes of hepatic inflow occlusion, AR or Ringer's lactate solution (LR) was administered. Ketone body concentrations in arterial and renal venous blood and renal cortical and medullary tissue were measured enzymatically. Results are expressed as means +/- SEM. At 20 minutes of hepatic inflow occlusion, arterial ketone body concentrations decreased to 38% of preischemic values with the LR infusion but increased under AR administration and were four times higher than that with LR. The renal arteriovenous difference in ketone body concentration was 16 +/- 14 micromol/ml before hepatic inflow occlusion and -52 +/- 14 with AR administration, indicating that renal ketogenesis occurred during hepatic ischemia. Total ketone body concentrations in the renal cortex and medulla were 56 +/- 6 and 61 +/- 5 micromol/g, respectively with LR, but increased to 186 +/- 29 and 248 +/- 25 micromol/g, respectively during AR administration. The concentration in the medulla was higher (p = 0. 12) than that in the cortex but did not reach statistical difference. Renal ketogenesis increases during hepatic inflow occlusion with AR administration. It is likely that the enhancement of ketogenesis takes place predominantly in the medulla of the kidney.

Renal Effects of α-Ketoglutarate Early After Coronary Operations

Background. α-Ketoglutarate (α-KG) is a Krebs cycle intermediate and the carbon skeleton of glutamate. α-Ketoglutarate has provoked interest in heart surgery because of its proposed critical role in myocardial metabolism. This study investigates the role of α-KG in renal function after cardiac surgical procedures.Methods. Twenty-two patients with normal preoperative renal function were included in a prospective, randomized, and controlled study. Eleven patients received intravenous infusion of 30 g α-KG/hour after the operation. Measurements were performed before operation, immediately after operation, and after 30 minutes of α-KG infusion.Results. Renal blood flow was higher during α-KG infusion, 297% ± 97% (of preoperative value), than in controls, 125% ± 20% (p < 0.05). Filtration fraction was lower (12.3% ± 0.05% versus 17.2% ± 1.1%, p < 0.01), which prevented a significant difference in glomerular filtration rate. The renal arteriovenous differences of lactate, glutamate, glutamine, and glycine changed toward a net release during α-KG infusion.Conclusions. Infusion of α-KG enhances renal blood flow early after coronary surgical procedures in patients with normal renal function. The mechanism is unclear, but could be associated with primarily metabolic effects, and may potentially convey a beneficial effect for renal function.

Concentrations, release, and disposal of insulin-like growth factor (IGF)-binding proteins (IGFBP), IGF-I, and growth hormone in different vascular beds in patients with cirrhosis.

The liver is thought to be the major source of circulating insulin-like growth factor (IGF-I) and IGF-binding protein-1 (IGFBP-1), whereas the primary production site of circulating IGFBP-3 remains unknown. As other tissues may contribute to the circulating pool of IGF-I and IGFBP, the aim of the present study was to assess the hepatic and renal arterio-venous difference and production rates of IGF-I, IGFBP-1, IGFBP-3, and GH in cirrhotic patients (n = 22) and matched control subjects (n = 27). IGFBP-1 and -3, IGF-I, and GH levels were measured by RIA in hepatic, renal, and peripheral veins and in the femoral artery. Levels of IGFBP-1 to -4 were additionally determined by Western ligand blotting. Hepatic venous IGFBP-1 was significantly increased in the cirrhotic patients (mean +/- SEM, 33.6 +/- 9.1 vs. 10.4 +/- 1.9 micrograms/L; P < 0.001), and arterio-renal-venous extraction was significant in both patients (6 +/- 2%; P < 0.01) and controls (11 +/- 1%; P < 0.001). Conversely, IGFBP-3 was decreased in the cirrhotic patients (1265 +/- 149 vs. 2712 +/- 137 micrograms/L; P < 0.001). IGFBP-3 correlated significantly with the wedged hepatic venous pressure (r = -0.49; P < 0.05), serum aspartate aminotransferase (r = -0.66; P < 0.01), serum bilirubin (r = -0.65; P < 0.01), serum albumin (r = 0.64; P < 0.01), and the Child score (r = -0.57; P < 0.01). IGF-I was significantly lower in the cirrhotics (57 +/- 10 vs. 143 +/- 11 micrograms/L; P < 0.001). No significant IGFBP-3 proteolysis was demonstrated in cirrhotics or controls. No significant differences were found in the values obtained simultaneously from hepatic, renal, and brachial veins or femoral artery, which suggests that no major net production or release of IGFBP-3 or IGF-I occurs in these tissues. No differences in IGFBP-2 or IGFBP-4 determined by Western ligan blot were found between patients and controls. The IGF-I concentrations correlated significantly with parameters of biochemical liver function. Basal GH concentrations were significantly higher in the cirrhotics (1.19 +/- 0.13 vs. 0.58 +/- 0.08 micrograms/L; P < 0.001). A significant hepatic disposal of GH was found in the patients (P < 0.05) and controls (P < 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Glutamine synthesis from glucose and ammonium chloride by guinea-pig kidney tubules

1. At a physiological concentration (5 mM), glucose was found to be metabolized by isolated kidney cortex tubules prepared from fed guinea pigs. 2. The release of 14CO2 from [U-14C]glucose indicated that oxidation of the glucose carbon skeleton represented about 50% of the glucose removed; significant amounts of lactate and glutamine also accumulated. 3. Addition of 0.1-10 mM NH4Cl led to a dose-dependent stimulation of glucose metabolism which was accompanied by a large increase in lactate and glutamine accumulation and, to a lesser extent, in glucose oxidation. 4. Comparison of the release of 14CO2 from [1-14C]- and [6-14C]glucose indicates that, in both the absence and the presence of NH4Cl, the pentose phosphate shunt was only a minor pathway of glucose metabolism. 5. The central role of pyruvate carboxylase in the conversion of glucose carbon into glutamine carbon was demonstrated by using a bicarbonate-free medium and measuring the fixation of 14CO2 from [14C]bicarbonate, which was recovered mostly at C-1 of glutamine plus glutamate. 6. The NH4Cl-induced stimulation of glucose removal was secondary not only to increased glutamine synthesis, as shown by the effect of methionine sulphoximine, an inhibitor of glutamine synthetase, but also to the stimulation of phosphofructokinase activity by NH4Cl. 7. Renal arterio-venous difference measurements revealed that, in vivo, the guinea-pig kidney removed glucose from the circulating blood, which suggests that glucose carbon may contribute to the carbon skeleton of the glutamine released by this organ.

Renal serine production in vivo: effects of dietary manipulation of serine status

Renal serine production in rats was quantitated by simultaneously measuring renal blood flow and the renal arteriovenous difference for this amino acid. The rate of synthesis was 0.24 +/- 0.02 mumol.min-1.100 g-1 in rats fed a diet containing 12% casein. This rate was not altered by the inclusion of an additional 1% serine in the diet for 7 days or by acute infusion of serine, although both protocols increased blood serine by 50%. When rats were fed a diet in which protein was entirely replaced by crystalline amino acids the rate of renal serine production was also 0.25 +/- 0.05 mumol.min-1.100g-1. Omission of serine or both serine and glycine from this diet did not alter the rate of renal serine synthesis. Renal serine production does not respond to the serine content of the diet.

Renal Disposition of Amylase, Lipase, and Lysozyme in the Dog

Normal adult dogs were given intravenously lysine hydrochloride to abolish renal tubular reabsorption. The treatment caused tubular proteinuria. Once forced diuresis was established, fractional clearances for amylase, lipase, and lysozyme increased five-, 18-, and 857-fold over the baseline values, respectively. There was relatively little tubular reabsorption of amylase, and urinary amylase activity remained low. A renal arteriovenous difference in amylase activity was not present. Urinary amylase activity could not be reactivated by the addition of serum or treatment with dithiothreitol. Urinary inhibitors of amylase activity were not detected. Immunoreactive urinary amylase did not exceed kinetically measured urinary amylase. Therefore, the presence of irreversibly inactivated amylase did not explain the low fractional clearance of amylase. A small amount of serum macroamylase was present, but macroamylasemia did not account for canine amylase failing to pass the glomerular filter. It appears that the renal loss of amylase in the dog is not an important excretory route.

The influence of contrast medium dose on filtration fraction in the rabbit kidney.

We have examined the effect of dose on contrast medium-induced reductions in glomerular filtration in anesthetized rabbits. The fraction of renal plasma flow that is filtered, the filtration fraction, was directly measured by the renal arteriovenous difference method using technetium-99m (99mTc) (Sn) DTPA as the tracer, arterial and renal venous extracorporeal shunts, a gamma camera and a computer. Filtration fraction (FF) was measured each 30 seconds before and after contrast medium (sodium/methylglucamine diatrizoate) was injected in 15 seconds at a dose of 0.5, 1.0 or 2.0 ml/kg, IV. In six animals that had a control FF of 0.19 +/- 0.01 there was a dose-related decrease in FF. The largest dose reduced FF by 53.3%. In three other animals that had a low control FF (0.07 +/- 0.01), the largest dose induced an even greater 71.0% decrease in FF. These data suggest that attempts at increasing contrast excretion by injecting larger doses will be offset, at least in part, by larger reductions in glomerular filtration, and that this effect may be greater when glomerular function is impaired.

Rapid renal clearance of immunoreactive canine plasma myoglobin.

Rates and mechanisms of myoglobin removal from plasma were examined in closed-chest dogs, using disappearance patterns of immunoreactivity and radioactivity after i.v. canine myoglobin radiolabeled with 125I. Arterial immunoreactive myoglobin concentration decreased monoexponentially over a 2-decade range, with rate constants of disappearance averaging -0.080 +/- 0.014 min-1 (+/- SD) (corresponding to half-times of disappearance of 8.9 +/- 1.5 min). Renal arteriovenous difference in immunoreactive myoglobin concentration documented extraction of the parent molecule, with extraction ratios averaging 0.36 +/- 0.06. Renal venous specific activity increased a few minutes after myoglobin administration, consistent with discharge from the kidney of nonimmunoreactive radiolabeled peptides of the parent molecule. Arterial disappearance of 125I was subsequently delayed in relation to immunoreactive myoglobin. Urinary recoveries of immunoreactive parent molecule and radiolabeled constituents were limited, averaging 2.5 +/- 1.1% and 12 +/- 1.1% over a 6-hour period. Arterial rate, constants of disappearance of immunoreactive myoglobin decreased markedly with decreases in renal perfusion produced by obstruction of renal arterial inflow. We conclude that myoglobin entering the vascular space is normally cleared rapidly by renal catabolism. Seven myoglobin concentration-time patterns during acute myocardial infarction directly reflect patterns of protein entry into the vascular space after release from injured tissue.

Metabolism of plasma mevalonate in rats and humans.

A circadian rhythm in plasma mevalonate was identified in human subjects. This variation, over a 5-fold range, is paralleled by a rhythm in urinary excretion. No such diurnal change in plasma mevalonate was observed in schedule-fed, light-cycled rats, despite the presence of a pronounced rhythm in liver HMG-Coa reductase and sterol synthesis. A linear correlation was found between liver HMG-CoA reductase activity and the rate of hepatic sterol synthesis. Sterol synthesis accounted for 59% of the HMG-CoA reductase activity. A 4-fold increase in plasma mevalonate following bilateral nephrectomy did not feed back on liver HMG-CoA reductase. Turnover rates for circulating R- and S-mevalonate were determined by the kinetics of tritiated tracers. S-Mevalonate exhibited first-order kinetics with a T 1/2 of 19 to 23 min, while R-mevalonate kinetics could be resolved into two phases with half-lives of 9 and 42 min. The renal uptake of circulating mevalonate was measured by the initial rate of increase in plasma mevalonate immediately following bilateral nephrectomy; this was confirmed by determination of the renal arterio-venous difference. This value ranges between 500 and 600 pmol/min for a 250-g rat.

Acute acidosis and renal arteriovenous differences of glutamine in normal and adrenalectomized rats.

ARTICLESAcute acidosis and renal arteriovenous differences of glutamine in normal and adrenalectomized ratsR. P. Hughey, B. B. Rankin, and N. P. CurthoysR. P. Hughey, B. B. Rankin, and N. P. CurthoysPublished Online:01 Mar 1980https://doi.org/10.1152/ajprenal.1980.238.3.F199MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByRenal Ammonia Metabolism and Transport1 January 2013Renal Acidification MechanismsGlucocorticoids have a role in renal cortical expression of the SNAT3 glutamine transporter during chronic metabolic acidosisAnne M. Karinch, Cheng-Mao Lin, QingHe Meng, Ming Pan, and Wiley W. Souba1 January 2007 | American Journal of Physiology-Renal Physiology, Vol. 292, No. 1Proteomic analysis of the adaptive response of rat renal proximal tubules to metabolic acidosisNorman P. Curthoys, Lynn Taylor, Jason D. Hoffert, and Mark A. Knepper1 January 2007 | American Journal of Physiology-Renal Physiology, Vol. 292, No. 1Mechanism of increased renal gene expression during metabolic acidosisNorman P. Curthoys, and Gerhard Gstraunthaler1 September 2001 | American Journal of Physiology-Renal Physiology, Vol. 281, No. 3Specificity and functional analysis of the pH-responsive element within renal glutaminase mRNAOmar F. Laterza, and Norman P. Curthoys1 June 2000 | American Journal of Physiology-Renal Physiology, Vol. 278, No. 6Glutamine synthetase expression in rat lung is regulated by protein stabilityBrian I. Labow, Steve F. Abcouwer, Cheng-Mao Lin, and Wiley W. Souba1 November 1998 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 275, No. 5 More from this issue > Volume 238Issue 3March 1980Pages F199-F204 Copyright & PermissionsCopyright © 1980 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.1980.238.3.F199PubMed7369361History Published online 1 March 1980 Published in print 1 March 1980 Metrics

Glutamine metabolism in the kidney during induction of, and recovery from, metabolic acidosis in the rat.

Experiments were carried out on rats to evaluate the possible regulatory roles of renal glutaminase activity, mitochondrial permeability to glutamine, phosphoenolpyruvate carboxykinase activity and systemic acid-base changes in the control of renal ammonia (NH(3) plus NH(4) (+)) production. Acidosis was induced by drinking NH(4)Cl solution ad libitum. A pronounced metabolic acidosis without respiratory compensation [pH=7.25; HCO(3) (-)=16.9mequiv./litre; pCO(2)=40.7mmHg (5.41kPa)] was evident for the first 2 days, but thereafter acid-base status returned towards normal. This improvement in acid-base status was accompanied by the attainment of maximal rates of ammonia excretion (onset phase) after about 2 days. A steady rate of ammonia excretion was then maintained (plateau phase) until the rats were supplied with tap water in place of the NH(4)Cl solution, whereupon pCO(2) and HCO(3) (-) became elevated [55.4mmHg (7.37kPa) and 35.5mequiv./litre] and renal ammonia excretion returned to control values within 1 day (recovery phase). Renal arteriovenous differences for glutamine always paralleled rates of ammonia excretion. Phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase activities and the rate of glutamine metabolism (NH(3) production and O(2) consumption) by isolated kidney mitochondria all increased during the onset phase. The increases in glutaminase and in mitochondrial metabolism continued into the plateau phase, whereas the increase in the carboxykinase reached a plateau at the same time as did ammonia excretion. During the recovery phase a rapid decrease in carboxykinase activity accompanied the decrease in ammonia excretion, whereas glutaminase and mitochondrial glutamine metabolism in vitro remained elevated. The metabolism of glutamine by kidney-cortex slices (ammonia, glutamate and glucose production) paralleled the metabolism of glutamine in vivo during recovery, i.e. it returned to control values. The results indicate that the adaptations in mitochondrial glutamine metabolism must be regulated by extra-mitochondrial factors, since glutamine metabolism in vivo and in slices returns to control values during recovery, whereas the mitochondrial metabolism of glutamine remains elevated.

Insulin and the kidney.

Changes in renal function and structure are frequently observed in patients with diabetes mellitus. In the early phases of the disease, alterations in glomerular filtration rate, renal plasma flow, glomerular permeability and tubular capacity for glucose reabsorption occur. In the late stages of juvenile onset diabetes, renal failure is a common cause of death. For this reason, increasing attention is being paid to the possibility of long-term dialysis and renal transplantation in these patients. The kidneys play an important role in regulating insulin metabolism. The renal arteriovenous difference is approximately 30-45% and a linear relationship exists between the arterial insulin level and the renal arteriovenous concentration difference. The renal extraction of insulin is 200 ml/min in man, and it is estimated that 6-8 U are removed and degraded by the kidney in 24 h. The quantity of insulin in urine is small. However, its clearance is relatively constant over a wide range of serum concentrations and is 0.15-0.5 ml/min. The mean basal insulin excretion is 3.6 muU/mg creatinine, and a fourfold rise occurs following a glucose load. The urinary insulin values in neonates, children and patients with diabetes and renal failure are reviewed. In diabetic patients, progressive renal disease is accompanied by decreasing insulin requirements. In contrast, nondiabetic patients who develop renal failure frequently show abnormalities in carbohydrate metabolism, the commonest of which is a pseudodiabetic state.

Metabolism of proinsulin, insulin, and C-peptide in the rat.

The renal extraction and excretion of bovine proinsulin, insulin, and C-peptide and the contribution of the kidney to their total metabolic clearance rate (MCR) were studied in the rat. Metabolic clearance rates were measured by the constant infusion technique and plasma and urine concentrations of each polypeptide were determined by radioimmunoassay. The MCR of insulin (16.4+/-0.4 ml/min) was significantly greater than that of either proinsulin (6.7+/-0.3 ml/min) or C-peptide (4.6+/-0.2 ml/min). Metabolic clearance rates were independent of plasma levels over a range of steady-state plasma concentrations varying from 1 to 15 ng/ml.In contrast to the differences in their metabolic clearance rates, the renal disposition of the three polypeptides was similar, being characterized by high extraction and very low urinary clearance. The renal arteriovenous difference of proinsulin, insulin, and C-peptide averaged 36, 40, and 44%, respectively, and was linearly related to their arterial concentration between 2 and 25 ng/ml. When glomerular filtration was markedly reduced or stopped by ureteral obstruction, the renal extraction of proinsulin, insulin, and C-peptide was invariably greater than the simultaneously measured extraction of inulin, indicating that these polypeptides are removed from the renal circulation by both glomerular filtration and direct uptake from peritubular capillary blood. The fractional urinary clearance of each polypeptide never exceeded 0.6%, indicating that more than 99% of the amount filtered was sequestered in the kidney. The renal removal of proinsulin and C-peptide from the circulation accounts for 55 and 69% of their metabolic clerance rates, while the renal contribution to the peripheral metabolism of insulin was smaller, averaging 33%. This difference is due to the fact that insulin, but not the other two polypeptides, is metabolized to a significant extent by the liver. These results define the renal handling of proinsulin, insulin, and C-peptide in the rat and indicate that in this species the kidney represents a major site for insulin metabolism and is the main organ responsible for the degradation of proinsulin and C-peptide.

On the mode of action of diuretics II effects of ethacrynic acid on renal oxygen consumption and tubular sodium reabsorption in dogs

Urine volume, renal blood flow, glomerular filtration rate, tubular sodium reabsorption (TNa) and renal oxygen consumption (VO 2) have been investigated in anesthetized dogs before and after the administration of 5 mg/kg ethacrynic acid. After ethacrynic acid, sodium reabsorption was depressed from 96 to 71% of the filtered load whereas oxygen consumption remained constant. Mean renal blood flow was increased to 134% of the control level but renal arterio-venous difference of oxygen was lowered respectively. Thus the ratio TNa/VO 2 was decreased significantly The calculated equations for the regression lines were VO 2 = 0.022 TNa + 0.067 before and VO 2 = 0.035 TNa + 0.065 after injection of ethacrynic acid. The results are compatible with the hypothesis that ethacrynic acid does not directly inhibit the active sodium transport mechanism but rather influences cell membrane permeability.