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A Flyvbjerg

Publications and source records attributed to A Flyvbjerg.

At least 181 records · Page 10Linked to original sources
PubMed1993

IGF-II/Man-6-P receptors in rat kidney: apical localization in proximal tubule cells.

The present study was performed to determine the localization of insulin-like growth factor II (IGF-II) binding in the rat nephron and, furthermore, to determine directly the distribution of the IGF-II/Man-6-P receptor in the proximal tubule. The IGF-II/Man-6-P receptor was visualized by immunohisto- and cytochemical techniques, and the binding of IGF-II was shown by light and electron microscope autoradiography applying 125I-IGF-II directly on cryosections. The tubular uptake of IGF-II was studied by autoradiography after in vivo injection of 125I-IGF-II. The light microscope immunolabeling was confined to a relatively narrow band in the apical part of the proximal tubule cells just below the brush border, and was strongest in the first portion of the proximal tubule, segment 1 (S1), with decreasing intensity in segment 2 (S2) and weaker in segment 3 (S3). Several cytoplasmic bodies were labeled but no label was observed in the basolateral part of the cells. We did not detect any labeling of glomeruli or other segments of the nephron. Electron microscope immunocytochemistry in the proximal tubule revealed a strong labeling in apical endocytic invaginations, small endocytic vacuoles, and large endocytic vacuoles, weaker in lysosomes and dense apical tubules. Light microscope autoradiography after incubation of cryosections with labeled IGF-II demonstrated an intense labeling just beneath the brush border, especially in S1 of the proximal tubule, and, in addition, the corresponding electron microscope autoradiography revealed an intense labeling over large endocytic vacuoles and lysosomes. These results were confirmed and extended by competitive binding experiments and quantitative immunocytochemistry. After i.v. injection of 125I-IGF-II autoradiographic grains were almost exclusively observed in the electronmicroscope over endocytic vacuoles and lysosomes in the S1 of the proximal tubule. The present study shows that the IGF-II/Man-6-P receptor is located in components of the vacuolar system in the apical cytoplasm of rat renal proximal convoluted tubule cells, mainly in S1. This localization was seen to be consistent using various immunolabeling and autoradiographic techniques in vivo and in vitro.

Animals↗
PubMed1993

Inhibition of renal ornithine decarboxylase activity prevents kidney hypertrophy in experimental diabetes.

The selective ornithine decarboxylase (ODC) inhibitor difluoromethyl ornithine (DFMO) was used to investigate the role of polyamines in initial diabetic renal enlargement. ODC activity in kidneys from diabetic animals was increased (fivefold) 24 h after diabetes induction (P < 0.05), and throughout the study (7 days) the activity remained 2- to 3-fold elevated (P < 0.05). Insulin treatment normalized renal ODC activity, whereas DFMO treatment totally inhibited the kidney ODC activity. The kidney weight in diabetic rats was 21% higher than that of control rats (1,074 +/- 35 mg and 889 +/- 16 mg, P < 0.001). Insulin treatment normalized kidney weight (847 +/- 13 mg). Despite unaltered diabetic metabolic aberrations the kidney weight in DFMO-treated diabetic rats was normalized (911 +/- 7 mg). In conclusion, the ODC activity in diabetic kidneys undergoing hypertrophy was increased. Insulin treatment normalized both kidney weight and kidney ODC activity. Finally, selective inhibition of ODC activity by DFMO resulted in kidneys of normal size, despite unaltered diabetic metabolic aberrations. These findings support the hypothesis that polyamines play an important role in initial diabetic renal enlargement.

Animals↗
PubMed1993

Effects of IGF-I infusion on growth and muscle Na(+)-K+ pump concentration in K(+)-deficient rats.

K(+)-deficient rats and control rats were infused for 14 days with vehicle: acetic acid (AcA) or recombinant human insulin-like growth factor-I (IGF-I, 240 micrograms/day) by osmotic minipumps. IGF-I treatment of K(+)-deficient rats did not result in overall growth of carcass or muscles but in marked selective growth of adrenals (+42%) and spleen (+66%). In control rats, IGF-I induced increased body and muscle weight, tibia length, and thymus weight. K+ deficiency was associated with reduced serum IGF-I but unchanged thyroid status. IGF-I treatment of the K(+)-deficient rats restored serum IGF-I and decreased total 3,5,3'-triiodothyronine. In AcA-treated K(+)-deficient rats [3H]ouabain binding site concentration decreased by 63 and 43% in soleus and extensor digitorum longus (EDL) muscle, respectively, compared with the AcA-treated controls. IGF-I had no effect on the [3H]ouabain binding site concentration in the control group, but in K(+)-deficient rats a significant lowering of 26% was observed in EDL. K+ deficiency causes relative organ-specific resistance to the growth-promoting effects of IGF-I, comparable to the effects seen in protein-restricted rats. Reduced circulating IGF-I is not the only cause of the downregulation of Na(+)-K+ pumps in K+ deficiency, and IGF-I treatment of control animals in vivo has no stimulatory effect on the synthesis of Na(+)-K+ pumps.

Adrenal Glands↗
PubMed1993

Luminal and basolateral uptake and receptor binding of IGF-I in rabbit renal proximal tubules.

The aim of the present study was to quantify and compare the luminal and basolateral binding and uptake of 125I-labeled insulin-like growth factor I (IGF-I) by means of 1) isolated, perfused, proximal tubules combined with electron microscope autoradiography and 2) luminal and basolateral membrane vesicles from rabbit proximal tubules. 125I-IGF-I was added to isolated perfused proximal tubules for 30 min in concentrations of 1.6-3.9 micrograms/l to either the perfusate or the bath. The luminal and basolateral uptake in 30 min averaged 447 and 410 fg/mm, respectively. About 20% of the luminally absorbed IGF-I was digested. Addition of excess unlabeled IGF-I (10(-7) M) to the bath produced complete inhibition of the basolateral binding/uptake, whereas no inhibition of the luminal uptake was seen. Electron microscope autoradiography showed that IGF-I after luminal endocytic uptake to a large extent was transported into lysosomes. After basolateral exposure the major portion of the grains was found over the basolateral cell membrane; however, a significant amount was located over endocytic vacuoles and lysosomes in both apical and basal parts of the cells. In both luminal and basolateral membrane vesicles, single-class, high-affinity binding sites for IGF-I were found with dissociation constants of 6.3 and 5.7 nM, respectively. Specific binding capacities averaged 2.7 and 25.7 pmol IGF-I/mg protein in luminal and basolateral vesicles. The biochemical data suggest an asymmetric distribution of specific IGF-I receptors in the luminal and basolateral membranes, with a greater abundance of receptors in the latter. The extensive basolateral endocytic binding/uptake of IGF-I compared with that of the luminal in isolated perfused tubules differs considerably from the processing of other peptide hormones.

Animals↗
PubMed1993

Effects of growth hormone and thyroxine on kidney insulin-like growth factor-I and renal growth in hypophysectomized rats.

The effects of treatment for 11 days with human growth hormone (hGH; 140 micrograms/day), thyroxine (T4; micrograms/day) and hGH+T4 on renal growth and content of insulin-like growth factor-I (IGF-I) in hypophysectomized rats have been compared with saline-treated hypophysectomized animals and intact control animals. Right kidney weight and kidney weight/body weight ratio remained low in the saline-treated group (313 +/- 9 mg vs 694 +/- 28 mg in controls on day 11, P < 0.001 and 3.4 +/- 0.12 x 10(-3) vs 4.2 +/- 0.10 x 10(-3), P < 0.005 respectively). In T4- and hGH-treated animals, kidney weight gain was similar (to 420 +/- 14 and 450 +/- 22 mg on day 11 respectively, P > 0.05), whilst the increase was greater in the group given hGH+T4 (to 572 +/- 34 mg, P < 0.001 compared with hGH- and T4-treated groups). The kidney weight/body weight ratio became normal in the T4- and hGH+T4-treated animals but remained low in the hGH-treated group. The renal content of IGF-I was low in the saline-treated animals throughout the study (92 +/- 10 ng/g on day 11 vs 219 +/- 8 ng/g in control animals, P < 0.001), but increased to a maximum of 88% above baseline on day 1 in the group given T4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of growth hormone on the inflammatory activity of experimental colitis in rats.

The effect of daily treatment with 2.0 mg biosynthetic human growth hormone per kilogram body weight or isotonic NaCl (controls) on experimental colitis was investigated in rats. Colonic inflammation was induced by instillation of trinitrobenzene sulfonic acid (TNB) intraluminally into the left colon. Untreated NaCl-instilled rats were used for comparison with intact colon. Four days after TNB instillation the growth hormone-treated rats had lower macroscopic and microscopic damage scores and less infiltration of neutrophils, measured as myeloperoxidase activity (MPO), than controls. The biomechanical properties of the colon showed that the breaking strength and energy absorption were reduced in the control rats with colitis compared with intact colon, whereas the rats treated with growth hormone had unchanged strength and energy absorption. The differences in MPO activity, damage scores, and biomechanical properties were associated with a higher concentration of insulin-like growth factor I in serum from growth hormone-treated rats after 4 days than controls. Finally, the growth hormone-treated rats regained their initial body weight after 7 days, in contrast to the body weight of control rats, which remained 11% lower than their initial body weight.

Animals↗
PubMed1992

Transient increase in renal insulin-like growth factor binding proteins during initial kidney hypertrophy in experimental diabetes in rats.

The insulin-like growth factors, insulin-like growth factor I and insulin-like growth factor II are bound to six distinct classes of insulin-like growth factor binding proteins (IGFBPs) in the circulation and in extracellular fluids. Diabetic renal hypertrophy is preceded by a transient increase in kidney insulin-like growth factor I suggestive of a renotropic function for insulin-like growth factor I. In order to examine a possible involvement of IGFBPs in initial diabetic kidney growth and in kidney insulin-like growth factor I accumulation, we studied rat kidney IGFBPs by ligand blotting during the first 4 days after induction of diabetes. Six distinct bands were identified in kidney and liver tissue with apparent molecular weight values of 38-47 (doublet), 34, 30, 24 and 20 kDa. The 38-47 kDa doublet band probably corresponds to the insulin-like growth factor binding subunit of IGFBP-3, the 24 kDa band to IGFBP-4 and the 30 kDa band to IGFBP-1 and/or IGFBP-2, as these IGFBPs in rats have similar molecular weight. In untreated diabetic rats a transient increase in the kidney 30 kDa band was demonstrable 24 h after induction of diabetes with a maximal rise (two-fold) after 48 h, followed by a decrease to baseline values after 4 days. In untreated diabetic rats the 38-47 kDa doublet band also increased (two-fold) in kidney during the first 2 days after induction of diabetes, followed by a subsequent decrease. Insulin-treatment prevented both the increase in the 30 kDa and in the 38-47 kDa bands.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Obstructive nephropathy in the pig. Possible roles for insulin-like growth factor I.

Kidney growth was investigated in 30-kg pigs after 72 h of unilateral ureteral obstruction. The data were compared to control kidneys from normal non-operated pigs at same weight. Kidney wet weight was determined. Cortex and medulla were separated, and from both regions RNA, DNA, protein and kidney tissue insulin-like growth factor I was determined. Unilateral obstruction caused a doubling of the wet hydronephrotic kidney weight and an ipsilateral 76% increase in total kidney protein content. RNA increased by 45% in the cortex and 76% in the medulla. Kidney protein in the contralateral cortex increased by 23% and RNA by 42%. In the hydronephrotic kidney DNA was reduced by 13% in the cortex and by 21% in the medulla. Contralaterally, DNA was the same as in the controls. Mean kidney insulin-like growth factor I increased sevenfold in the ipsilateral medulla but in the cortex it was the same as in the controls. Serum insulin-like growth factor I concentration was 1.7 +/- 1.1 micrograms/l in the hydronephrotic animals and 1.2 +/- 0.8 micrograms/l in controls. At this stage of obstruction, our data demonstrate (1) hydronephrotic growth that is most probably hyperplastic in the medulla, associated with an increase in medullary insulin-like growth factor I, (2) hyperplastic growth in the cortex, and (3) contralateral kidney growth that is mainly hypertrophic after 72 h of contralateral ureteral obstruction.

Animals↗
PubMed1992

Octreotide and diabetes: theoretical and experimental aspects.

Diabetes is characterized by paradoxical hypersomatotropinemia and hyperglucagonemia. The latter appears to enhance the tendency in imperfect metabolic control to reduce nitrogen balance, and the former appears to accelerate the deterioration of carbohydrate and lipid metabolism, and also to induce peripheral insulin resistance and hyperinsulinemia. In addition to direct metabolic effects, increasing evidence points to an association between hypersomatotropinemia and a number of metabolically dependent, characteristic functional abnormalities linked to the development of late diabetic manifestations. These include increased capillary fragility, lipid and hemostatic aberrations, tissue hyperperfusion, including increased cardiac output and renal plasma flow, and kidney hypertrophy. In theory, octreotide's actions could reduce these aberrations, and, in fact, this has been confirmed in recent experimental trials.

Animals↗
PubMed1992

Increased ornithine decarboxylase activity in kidneys undergoing hypertrophy in experimental diabetes.

Renal hypertrophy and hyperfiltration are early manifestations of human and experimental diabetes that may contribute to the late development of diabetic nephropathy. The biochemical events resulting in kidney growth in the diabetic state are completely unknown. Since growth of various tissues is accompanied by increased formation of polyamines, we studied whether polyamines were involved in the growth of the kidney observed in diabetic rats. This was done by measuring the activity of the rate-limiting enzyme in the polyamine pathway (ornithine decarboxylase; ODC) in kidneys from control, diabetic and insulin-treated diabetic animals. The ODC activity in the kidney was increased in the diabetic animals with a maximal rise 24 h after diabetes induction (6-fold, P less than 0.01); the activity thereafter declined. However, on day 14 the activity was still significantly elevated (2.5-fold, P less than 0.05). In insulin-treated diabetic animals the kidney ODC activity was only increased 3-fold (P less than 0.05) after 24 h, and for the rest of the study period the activity was about 1.8-fold higher than in control rats. After 14 days the kidneys from diabetic rats were significantly larger than kidneys from both control and insulin-treated diabetic rats, 1066 +/- 43 mg vs. 904 +/- 16 mg and 959 +/- 36 mg, respectively (P less than 0.01). For comparison, the ODC activity was also investigated in muscle. However, in muscle from diabetic animals the ODC activity declined steadily during the 14 days to 34% of control values (P less than 0.01), and insulin treatment completely normalized the ODC activity in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Octreotide administration in diabetic rats: effects on renal hypertrophy and urinary albumin excretion.

Initial renal hypertrophy in experimental diabetes is prevented by administration of a long-acting somatostatin analogue octreotide (SMS). To investigate the long-term effects of SMS on renal hypertrophy and urinary albumin excretion (UAE), streptozotocin-diabetic and non-diabetic rats were treated with two daily subcutaneous injections of SMS (100 micrograms x 2) for six months. Untreated diabetic and non-diabetic animals were used as reference groups. No differences were seen between the two diabetic groups in respect to body weight, food intake, blood glucose levels, urinary glucose output, hemoglobin A1C(HbA1C), fructosamine, serum growth hormone (rGH) or creatinine clearance, but kidney weight (896 +/- 36 vs. 1000 +/- 24 mg, P less than 0.02), UAE (417 +/- 131 vs. 1098 +/- 187 micrograms/24 hr, P less than 0.02), kidney insulin-like growth factor I (IGF-I) (167 +/- 16 vs. 239 +/- 17 ng/g, P less than 0.01) and serum IGF-I (301 +/- 26 vs. 407 +/- 17 micrograms/liter, P less than 0.01) were all reduced in the SMS-treated diabetic animals when compared to the untreated diabetic group. In non-diabetic rats SMS reduced body weight (274 +/- 3 vs. 293 +/- 5 g, P less than 0.01), kidney weight (695 +/- 9 vs. 764 +/- 17 mg, P less than 0.01), UAE (83 +/- 29 vs. 364 +/- 114 micrograms/24 hr, P less than 0.02), kidney IGF-I (202 +/- 12 vs. 280 +/- 12 ng/g, P less than 0.01), serum IGF-I (428 +/- 21 vs. 601 +/- 54 micrograms/liter, P less than 0.01) and serum rGH (67 +/- 6 vs. 126 +/- 27 micrograms/liter, P less than 0.05) when compared to untreated controls. When kidney weights were expressed in relation to body weight no difference was found between SMS-treated and untreated controls, while the difference between SMS-treated and untreated diabetic animals was still present (P less than 0.01). In conclusion, chronic administration of SMS has abating effects on diabetic renal hypertrophy and UAE, and thus indicates that SMS may reduce development of diabetic kidney lesions in experimental diabetes. The long-term suppressive effects of SMS on renal enlargement and UAE may in part be mediated through reduction in circulating and kidney IGF-I levels.

Albuminuria↗
PubMed1992

Effects of growth hormone on growth and muscle Na(+)-K+ pump concentration in K(+)-deficient rats.

K(+)-deficient rats and control rats were injected for 16 days with saline or human growth hormone (hGH, 200 micrograms/day). hGH treatment of K(+)-deficient rats resulted in increased weight gain and soleus muscle weight. Extensor digitorum longus (EDL) muscle weight and tail and tibia length were unchanged. In control rats, hGH induced an increase in all weight and length parameters. K+ deficiency was associated with reduced serum insulin-like growth factor I (IGF-I) and serum insulin but unchanged total 3,5,3'-triiodothyronine (TT3) and total thyroxine. hGH treatment of the K(+)-deficient rats restored serum IGF-I, but not serum insulin, and decreased TT3. In saline-treated K(+)-deficient rats [3H]ouabain binding site concentration decreased by 44 and 39% in soleus and EDL muscle, respectively, as compared with the saline-treated controls. hGH had no effect on the [3H]ouabain binding site concentration in the K(+)-deficient group, but, in control rats, increases of 11 and 8% were observed in soleus and EDL muscle, respectively. When the increase in muscle weight was taken into account, this amounted to relative increases of 24 and 30%, respectively. Low circulating GH and IGF-I levels are not the sole explanation for the growth retardation in K+ deficiency. GH/IGF-I stimulate the synthesis of Na(+)-K+ pumps in rats with an otherwise normal hormonal status.

Animals↗
PubMed1992

Kidney IGF-I and renal hypertrophy in GH-deficient diabetic dwarf rats.

Insulin-like growth factor I (IGF-I) has been proposed as a renotropic factor in initial diabetic kidney growth. To examine the effects of an isolated growth hormone (GH) and IGF-I deficiency on diabetic renal hypertrophy, dwarf rats were made diabetic and studied over a period of 7 days. Diabetic dwarf rats treated with human GH (hGH) or insulin and diabetic rats with intact pituitary were used as controls. In diabetic control animals kidney weight had increased by day 2 (P less than 0.01), and the increase amounted to 27% after 7 days, whereas untreated diabetic dwarf rats had a slower and lesser degree of kidney weight increase, reaching significance on day 7 only, amounting to 8%. hGH administration in diabetic dwarf rats increased the kidney weight on day 7 when compared with untreated diabetic dwarf rats (P less than 0.05) and was 19% over that of insulin-treated diabetic dwarf rats. The glomerular volume had increased by 43% in untreated diabetic control rats at day 7, compared with a 29% increase in untreated diabetic dwarf rats (P less than 0.05). hGH administration in diabetic dwarf rats increased the glomerular volume by 46%, comparable to the increase seen in diabetic control animals. Kidney IGF-I was increased on day 2 by 51 and 46% in saline- and hGH-injected diabetic dwarf rats, respectively, but a significantly higher increase in kidney IGF-I amounting to 96% was seen in diabetic control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Insulin-like growth factor I in initial renal hypertrophy in potassium-depleted rats.

We investigated insulin-like growth factor I (IGF-I) in the kidney during the initial renal enlargement induced by dietary K depletion in rats. Kidney weight increase was significant after 3 days of K depletion and amounted to 29% after 7 days compared with pair-fed controls [839 +/- 34 vs. 648 +/- 17 mg (SE), P less than 0.01]. The kidney growth occurred despite almost complete arrest in body weight gain in K-depleted animals (8 +/- 3 vs. 34 +/- 4 g/7 days in controls, P less than 0.01). Whole kidney protein, RNA, and DNA estimations indicated that cellular hypertrophy during the first 4 days was followed by hyperplasia. Immunoassayable kidney IGF-I concentration increased by 106% (673 +/- 30 vs. 327 +/- 14 ng/g, P less than 0.01) in K-depleted animals 24 h after induction of K depletion, stayed elevated until day 4, and returned to control levels on day 7. After K depletion for 24 h, IGF-I immunostaining was markedly increased in the medullary parts of the collecting ducts from K-depleted animals, whereas kidney IGF-I gene expression (IGF-I mRNA) had decreased by 36%. The increase in total kidney IGF-I concentration and immunostainable IGF-I in collecting ducts in kidneys from K-depleted rats precedes the renal hypertrophy and thereby suggests a renotropic role for IGF-I. The increase in kidney IGF-I concentration is not associated with increased IGF-I mRNA levels, indicating that non-transcriptional mechanisms may be responsible for the renal IGF-I accumulation.

Animals↗
PubMed1992

Lipid peroxidation in early experimental diabetes in rats: effects of diabetes and insulin.

The degree of lipid peroxidation was measured in organs from diabetic rats receiving no treatment, and in those from insulin-treated diabetic rats and controls. Lipid peroxidation was measured as organ content of malondialdehyde, a degradation product of polyunsaturated fatty acids. In the kidney, lipid peroxidation was increased after one week of diabetes; insulin treatment reduced the level of lipid peroxidation to levels lower than seen in controls. In the liver, diabetes caused an increased lipid peroxidation, which could be reversed by insulin; no additional effect of insulin was found. In heart and pancreas no effects of diabetes or insulin were demonstrated. The present paper provides evidence that lipid peroxidation is increased in the early stages of experimental diabetes and is reversible by insulin treatment. Hyperinsulinaemia may, in itself, counteract lipid peroxidation in kidney.

Animals↗
PubMed1992

Dose-dependent stimulatory effect of human growth hormone on the strength and collagen deposition of colonic anastomoses in the rat.

The effects of treatment with four different doses of biosynthetic human growth hormone (b-hGH; 0.125 mg kg-1 d-1, 0.5 mg kg-1 d-1, 2.0 mg kg-1 d-1, 8.0 mg kg-1 d-1) on the bursting strength and collagen deposition of rat colonic anastomoses were studied. Rats receiving 2.0 mg and 8.0 mg b-hGH demonstrated increases in the pre- and postoperative body weights, and the bursting strength and hydroxyproline content of the anastomotic segments in these groups were significantly higher than controls on day 4 postoperatively. The serum levels of insulin-like growth factor I (IGF-I) were significantly higher than the controls after four days of preoperative treatment in the groups receiving 2.0 mg and 8.0 mg b-hGH, and postoperatively the IGF-I levels were significantly higher than those of the controls in the groups receiving 0.5 mg, 2.0 mg and 8.0 mg b-hGH per kg. Consequently, positive correlations were found between treatment doses of b-hGH and anastomotic defatted dry weight, hydroxyproline content and bursting strength of colonic anastomoses.

Anastomosis, Surgical↗
PubMed1992

Effects of short-term growth hormone treatment on PTH, calcitriol, thyroid hormones, insulin and glucagon.

We measured changes in serum insulin-like growth factor-1 (IGF-1), calcitriol, parathyroid hormone (PTH), thyroid hormones, insulin, and plasma glucagon in response to seven days of treatment with a pharmacological dosage of recombinant human growth hormone (r-hGH) (0.1 IU/kg sc twice daily) or placebo in 20 normal male volunteers to evaluate whether the effect of r-hGH on biochemical bone markers could be attributed to changes in these hormones. Serum IGF-1 (p < 0.001) and vitamin D-binding protein (p < 0.001) increased steadily during treatment returning to baseline at day 14. Total calcitriol (p < 0.01) and free calcitriol index (p < 0.001) increased transiently at day 4. Furthermore, serum insulin (p < 0.001) and both total (p < 0.001) and free triiodothyronine (p < 0.02) increased during treatment, while serum PTH and plasma glucagon remained unchanged. In conclusion, pharmacological doses of r-hGH increased not only IGF-1 but also free-calcitriol index, insulin, and free T3. The increase in these hormones may be co-responsible for some of the observed effects of r-hGH on bone turnover and calcium homeostasis.

Adult↗