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Biomedical subjects

R Hirschberg

Publications and source records attributed to R Hirschberg.

At least 37 records · Page 2Linked to original sources
PubMed1996

Insulin-like growth factor-I and insulin-like growth factor-binding proteins in the nephrotic syndrome.

Similar to findings in the nephrotic syndrome in humans, rats with the doxorubicin-induced nephrotic syndrome (which resembles minimal change disease) have reduced serum levels of insulin-like growth factor-I (IGF-I). This is mainly caused by glomerular ultrafiltration of IGF-I-containing binding protein complexes, primarily of a molecular weight of approximately 50 kilodaltons, and urinary losses of the peptide. Despite urinary excretion of IGF-binding protein (IGFBP)-2, serum levels are increased more than twofold in the nephrotic syndrome compared with controls, because of increased synthesis of this binding protein by the liver. In contrast, the liver synthesis of IGFBP-3, the predominant binding protein in normal serum, is unchanged in the nephrotic syndrome. However, binding and serum levels of IGFBP-3 are reduced in nephrotic rat serum, apparently due to proteolytic degradation of IGFBP-3. The glomerular ultrafiltration of IGF-I, which leads to biologically significant IGF-I concentrations of about 1.35 nM in proximal tubule fluid, may have metabolic consequences, such as increased tubular phosphate absorption. Hypothetically, tubule fluid IGF-I may also contribute to progressive tubulointerstitial fibrosis which is sometimes present in protractive nephrotic glomerulopathies. The profound changes in the IGF-I/IGFBP system in the nephrotic syndrome may also contribute to systemic metabolic abnormalities and growth failure.

Animals↗
PubMed1996

Enalapril attenuates the renal hemodynamic effect of acetazolamide in patients with diabetes mellitus: possible implications for tubuloglomerular feedback.

Acetazolamide (ACTZ), a carbonic anhydrase inhibitor, causes a fall in renal plasma flow and glomerular filtration (GFR). It is generally believed that the tubuloglomerular feedback (TGF) mechanism is responsible. This study examined whether, in patients with diabetes mellitus, the renal hemodynamic response to ACTZ is intact and whether the angiotensin-converting enzyme inhibitor, enalapril, which would be expected to block TGF, attenuates this response to ACTZ. Six men with insulin-dependent diabetes mellitus lived in a clinical research center for 8 weeks and received enalapril 5-15 mg/day from the third through sixth week. At 2, 6 and 8 weeks p-aminohippurate (PAH) and inulin clearances were performed over eleven 30-min periods. ACTZ (150 mg) was given intravenously after 180 min. In both the pre- and postenalapril studies, PAH clearance fell after ACTZ administration (-60 +/- 15 and -66 +/- 20 ml/min/l1.73 m2, respectively, p < 0.05 for each study). In contrast, with enalapril treatment PAH clearance after ACTZ tended to rise (29 +/- 12 ml/ min/1.73 m2, p = 0.07). GFR after ACTZ fell during the pre- and postenalapril studies (-19 +/- 3 and -13 +/- 1 ml/min/1.73 m2, respectively, p < 0.05 for each study) but not with enalapril treatment (-6 +/- 3 ml/min/1.73 m2). After ACTZ was administered, estimated renal vascular resistance rose during both the pre- and postenalapril studies (p < 0.05 and p < 0.01, respectively) and fell with enalapril treatment (p < 0.05). These data indicate that enalapril alters the renal hemodynamic effects of ACTZ in patients with diabetes mellitus, possibly by inhibiting tubuloglomerular feedback.

Acetazolamide↗
PubMed1996

Growth hormone, the insulin-like growth factor system, and the kidney.

GH receptors, IGFs, and IGF-receptors are expressed in the kidney. Their location in the different parts of the nephron suggests autocrine or paracrine as well as endocrine modes of action. A lack of GH receptors and probably of IGF-I synthesis in glomeruli in vivo suggest that all glomerular GH and IGF-I effects are mediated by circulating IGF-I through endocrine modes. GH and IGF-I increase GFR in normal rats and humans, and increase phosphate and possibly sodium reabsorption in normal and diabetic subjects. During normal renal development GH, IGF-I, and IGF-II appear to play a role. GH and IGF-I cause kidney growth, and circulating and/or renal IGF-I appear to contribute to renal hypertrophy and compensatory renal growth in experimental animal models. GH may contribute also to glomerular sclerosis and progression of renal failure in experimental models. In patients with chronic renal failure such a role of endogenous or exogenous GH has not yet been convincingly proven. In chronic or acute renal failure and in the nephrotic syndrome there are complex abnormalities in the systemic and renal IGF/IGFBP-system. In chronic renal failure there is resistance to GH and IGF-I that can be overridden by pharmacological administration of each of the peptides. GH is used therapeutically in children with chronic renal failure to accelerate growth. GH and IGF-I may be useful agents to improve nitrogen balance and nutritional status in patients with chronic renal failure. In rats with ARF, administration of IGF-I accelerates the recovery of renal function. Whether this treatment is also successful in patients with ARF remains to be demonstrated by ongoing clinical trials.

Acute Kidney Injury↗
PubMed1996

Insulin-like growth factor I in the kidney.

Insulin-like growth factor I (IGF-I) is synthesized in renal glomeruli and distal tubules. The rather high serum IGF-I levels (20-40 nM) result mainly from synthesis in the liver. In the circulation > or = 99% of IGF-I is bound in binding protein complexes. IGF-I can act in the kidney by autocrine and paracrine as well as endocrine modes. IGF-I raises GFR through reducing arteriolar resistance and increasing LpA. The peptide also increases the tubule transport of phosphate both in vitro and in vivo. IGF-I has been associated with the initiation of hypertrophy in models of compensatory renal growth and may contribute to the accumulation of extracellular matrix proteins in the nephron in chronic renal diseases. In the nephrotic syndrome, IGF-I is ultrafiltered into tubule fluid in association with IGF-binding protein-2 and activates apical proximal tubule cell receptors.

Animals↗
PubMed1995

Effects of recombinant human insulin-like growth factor 1 on renal handling of phosphorus, calcium, and sodium in normal humans.

The effects of insulin-like growth factor 1 (IGF-1) on renal handling of phosphorus, calcium, and sodium were evaluated in eight healthy men while they lived in a clinical research center for slightly more than 5 days. Subjects received a continuous intravenous infusion throughout the study of 0.45% saline and 2.5% d-glucose at 50 mL/hr (group 1, four subjects) or 150 mL/hr (group 2, four subjects). Recombinant human IGF-1 (rhIGF-1), 60 micrograms/kg body weight, was injected subcutaneously three times daily for 10 doses from day 2 until the beginning of day 5. After commencing the rhIGF-1 injections, there was a marked decrease in the fractional excretion of phosphorus in both groups that was sustained throughout the study. Urine phosphorus excretion also decreased significantly on days 2 to 5 in group 1 and on day 2 in group 2. In group 1, the fractional excretion of calcium decreased on day 2; urine calcium did not change. The fractional excretion of sodium decreased on days 2 and 4; urine sodium decreased significantly only on day 2. In group 2, the fractional and absolute urine excretion of calcium did not change. Fractional sodium excretion was not altered, and urine sodium increased only on day 5. The average serum phosphorus, calcium, and sodium did not change from baseline in groups 1 or 2. The pattern of the circadian rhythms for serum concentrations, urine excretion, and fractional excretion of phosphorus and calcium did not appear to be affected by the rhIGF-1 injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Insulin-like growth factor I induces mesangial proliferation and increases mRNA and secretion of collagen.

Insulin-like growth factor I (IGF-1) is a peptide growth factor that is synthesized in cultured mesangial cells and induces hyperplasia. We tested whether incubation with IGF-1 at concentrations of 7 nM, 70 nM, and 350 nM stimulates mesangial cell extracellular matrix mRNA and protein levels, and whether it influences mesangial cell growth. Mesangial cells incubated with IGF-1 demonstrated a statistically significant increase in procollagen alpha 1(I) (100 +/- 13% vs. 147 +/- 12%, 154 +/- 10%, and 173 +/- 21%) and alpha 1(IV) 100 +/- 9% vs. 112 +/- 9%, 125 +/- 8%, and 172 +/- 28%) mRNA. Furthermore, IGF-1 also stimulated a statistically significant increment in alpha 1(IV) mRNA in isolated glomeruli when measured by Northern hybridization and corroborated by in situ hybridization experiments. In addition, mesangial cells incubated with IGF-1 induced a statistically significant increase in both secreted and cell associated type I (secreted: 100 +/- 5% vs. 127 +/- 9%, 148 +/- 5%, 178 +/- 11%; and cell-associated: 100 +/- 19 vs. 132 +/- 17%, 198 +/- 24%, and 314 +/- 17%) and type IV (secreted: 100 +/- 19% vs. 138 +/- 11%, 192 +/- 17%, 379 +/- 16%, and cell-associated: 100 +/- 8% vs. 139 +/- 10%, 206 +/- 16%, 310 +/- 15%) collagen. Thus, mRNA and collagen levels increased in a dose dependent fashion after incubation with IGF-1. Furthermore, IGF-1 stimulated hyperplasia but not hypertrophy in this in vitro system. These data suggest that IGF-1 may contribute to glomerular sclerosis by increasing mesangial matrix production as well as proliferation.

Animals↗
PubMed1995

Purification and characterization of Eikenella corrodens type IV pilin.

Eikenella corrodens is a gram-negative human pathogen associated with periodontal diseases and soft-tissue infections. Pilin was purified by association-dissociation and fast protein liquid chromatography; it had an apparent molecular mass of about 14.8 kDa and an N-terminal amino acid sequence reflective of type IV pilins. Antibodies to the purified protein reacted with pili on whole cells. This is the first report of purification of type IV pili/pilin from this organism. Other type IV pili are important virulence factors; we are currently investigating the biological role of pili in E. corrodens.

Amino Acid Sequence↗
PubMed1995

Insulin-like growth factor I and its binding proteins in the experimental nephrotic syndrome.

Insulin-like growth factor I (IGF-I) is present in serum in association with specific IGF-binding proteins (IGFBPs) primarily in a large (approximately 150K) ternary or a smaller (approximately 50K) binary protein complex or in the free form (< or = 1%). We hypothesized that glomerular proteinuria results in urinary excretion of IGF-I/IGF-binding protein complexes and that the nephrotic syndrome induces abnormal serum distribution and liver synthesis of IGF-binding proteins. In nephrotic rats, serum IGF-I levels are reduced compared with pair-fed control animals. In nephrotic rat serum, binding to IGFBP-3 is reduced and Western immune analysis demonstrates an approximately 27K fragment that does not bind IGF-I, suggesting in vivo proteolysis of IGFBP-3. In contrast, binding and serum levels of IGFBP-2 are increased in nephrotic rats, which results from increased synthesis in the liver. In Nagase analbuminemic rats, the IGF-I levels and IGFBP-distribution in serum are normal suggesting that the reduced albumin levels in the nephrotic syndrome do not cause the increased liver synthesis and serum levels of IGFBP-2. Nephrotic rat urine contains IGFBP-3 and IGFBP-2 as well as strong activity of an IGFBP-3 protease. Because the 150K ternary complex in serum but not the smaller binding protein complex is restricted to the intravascular space, the shift of binding from IGFBP-3 (ternary complex) to IGFBP-2 (binary complex) in nephrotic rat serum may help to maintain tissue availability despite the reduction in serum IGF-I levels.

Animals↗
PubMed1995

Effects of insulin-like growth factor I on phosphate transport in cultured proximal tubule cells.

In vivo, proximal tubule cells are exposed to insulin-like growth factor I (IGF-I) that is present in serum or in proximal tubule fluid. For example, in the nephrotic syndrome, proximal tubule fluid contains IGF-I at biologically meaningful concentrations in association with IGF-binding protein-2 (IGFBP-2). IGF-I has also been shown to decrease the urinary excretion of phosphate (Pi) in normal subjects. We hypothesized that IGF-I can raise tubule cell Pi absorption directly through an apical as well as a basolateral tubule receptor mechanism, specifically, through IGF-I (type I) receptors as compared to IGF-II (type II) or insulin receptors. Studies were performed in cultured proximal tubule cells that express high-affinity IGF-I receptors. Stimulation of cells selectively at the apical or basolateral membrane with IGF-I (10(-9) to 10(-7) mol/L) increases Pi absorption by up to 80%, but a significant counterdirectional Pi flux in the apical-to-basolateral direction does not occur. The effect of IGF-I on Pi transport appears to be specific inasmuch as the transport of alanine is not affected by the peptide. IGFBP-2 does not inhibit this effect of IGF-I, but the IGF-I-induced increase in Pi transport is inhibited by a neutralizing anti-IGF-I receptor monoclonal antibody. Exposure of the cells to IGF-II (10(-7) mol/L) but not to insulin selectively at the apical membrane tends to increase Pi transport, and this IGF-II effect is also blocked by the anti-IGF-I receptor antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1994

Scanning electron microscopy of Eikenella corrodens colony morphology variants.

Eikenella corrodens is a gram-negative, human pathogen which exhibits colony morphology variation. Scanning electron microscopy (SEM) was used to examine large (non-corroding) and small (corroding) colony variants from the type strain (ATCC 23834) and two clinical isolates (strains VA1 and CM1). Large colonies were large, flatter, and appeared relatively featureless compared to small colonies and had even, smooth colony margins. Small colonies were more raised from the medium surface, and often had a central raised region surrounded by flatter border. Cells on the surface of large colonies were more regularly arranged at the colony edge, and end-to-end rows of cells around the colony were seen in some strains. Cells in the center of the upper surface of small colonies were usually randomly arranged. Within cross sections of small colonies, cells were arranged randomly or perpendicular to the medium; in large colonies, cells were random or arranged horizontally. Amorphous, "slime" material was often seen covering groups of cells in large and small variants. An unusual variant, possibly a mutant, which combined features of both colony types was isolated.

Eikenella corrodens↗
PubMed1993

Effects of growth hormone and IGF-I on glomerular ultrafiltration in growth hormone-deficient rats.

In growth hormone deficient states glomerular filtration rate (GFR) and renal plasma flow rate (RPF) are both reduced. Studies were performed in growth hormone deficient rats to delineate the physiologic mechanisms by which growth hormone and IGF-I contribute to the regulation of glomerular function. Growth hormone deficient dw/dw rats received, for one week, subcutaneous infusions of vehicle, des(1-3)IGF-I or were injected i.m. with recombinant human growth hormone. Subsequent renal micropuncture and clearance studies revealed a low GFR and single nephron GFR (SNGFR) in vehicle treated growth hormone deficient animals. Glomerular function became normal with growth hormone or IGF-I treatment, respectively. Both treatments raised SNGFR by reducing arteriolar resistance and increasing the glomerular ultrafiltration coefficient. Furthermore, the two treatments also increased the glomerular tuft volume and the kidney weight which may contribute to the rise in SNGFR and GFR. It is concluded that, (1) in growth hormone deficiency glomerular function is reduced secondary to a high renal arteriolar resistance and a low ultrafiltration coefficient. Both result from a lack in IGF-I rather than the growth hormone deficiency state per se. (2) The growth hormone-IGF-I axis may contribute to the maintenance and physiologic regulation of GFR.

Animals↗
PubMed1993

Effects of insulin-like growth factor I on renal function in normal men.

Acute and chronic studies in rats have shown that administration of human recombinant insulin-like growth factor I (rhIGF-I) lowers renal vascular resistance and increases RPF, GFR and proximal tubular phosphate absorption. In the present study we examined the effects of subcutaneous injections of rhIGF-I on glomerular and tubular function in eight normal men. Individuals were studied for 5.5 consecutive days in a clinical research center while they ate a constant diet. Four subjects were studied in a non-volume expanded state (Group 1) and four individuals were evaluated during a saline load. From the second to the fourth day, subjects received subcutaneous injections of rhIGF-I, 60 micrograms/kg, at 0800, 1400 and 2000 hours. After commencing the rhIGF-I injections, serum IGF-I levels rose quickly and remained at about three to four times that of baseline throughout the period of rhIGF-I injections. In both the normal and the saline loaded subjects, renal vascular resistance decreased and RPF and GFR (PAH and inulin clearances) rose quickly and were clearly altered within six hours after starting the rhIGF-I injections. RPF had increased by 32 +/- 3% and 33 +/- 2% (grand mean +/- SEM) in the normal and the saline loaded subjects, and GFR rose by 22 +/- 3% and 36 +/- 4% in the two groups. In both groups the absolute and the fractional excretion of phosphate decreased markedly during rhIGF-I treatment, but the absolute and fractional excretion of calcium did not change. The urinary fractional and absolute excretion of albumin and IgG also increased, although slightly, with rhIGF-I injections. There was no consistent effect of IGF-I on tubular sodium handling. These findings demonstrate that in normal men subcutaneous injections of rhIGF-I greatly increase RPF, GFR, and tubular phosphorus reabsorption and enhances microproteinuria.

Albumins↗
PubMed1993

Recombinant human insulin-like growth factor-I accelerates recovery and reduces catabolism in rats with ischemic acute renal failure.

This study evaluated whether recombinant human insulin-like growth factor-I (rhIGF-I) enhances recovery of renal function and reduces catabolism in rats with ischemic acute renal failure (ARF). ARF and sham rats received subcutaneous injections of either rhIGF-I or vehicle three times daily starting 5 h after surgery. Serum creatinine and urea, which initially rose similarly in the ARF+vehicle and ARF+rhIGF-I rats, increased more slowly after commencing the rhIGF-I injections. 72 h after surgery, the ARF+rhIGF-I rats, in comparison with ARF+vehicle animals, showed significantly greater renal plasma flow and filtration fraction, a fivefold higher glomerular filtration rate, greater renal cortical IGF-I levels, increased proliferating cell nuclear antigen expression in proximal tubule nuclei and enhanced DNA synthesis in the renal cortex, corticomedullary junction, glomeruli, and tubules as demonstrated by [3H]thymidine incorporation and in corticomedullary junction tubules as determined by autoradiography. Estimated total nitrogen output (ETNO) was greater in ARF+vehicle than in ARF+rhIGF-I or sham rats throughout the study. ETNO in ARF+rhIGF-I rats returned to sham values by the second day after surgery. 72 h after surgery, protein degradation was increased and protein synthesis reduced in the epitrochlearis muscle of ARF+vehicle as compared with ARF+rhIGF-I or sham+vehicle rats. Thus, treatment with rhIGF-I starting 5 h after inducing ischemic ARF in rats increases recovery of renal function, enhances formation of new renal tubular cells, lowers protein degradation, and increases protein synthesis in skeletal muscle and reduces net catabolism.

Acute Kidney Injury↗
PubMed1992

The growth hormone-insulin-like growth factor I axis and renal glomerular function.

This study examined whether maneuvers that chronically raise or lower serum insulin-like growth factor I (IGF-I), within physiological and pathophysiological ranges, will affect glomerular hemodynamics. Pair-fed Munich Wistar rats received, for 6 to 7 days, continuous s.c. infusions of human recombinant IGF-I (rhIGF-I; 125 micrograms/day), vehicle, or s.c. injection of a synthetic growth hormone-releasing hormone antagonist (GHRH-ANT) (N = 7 in each group). Infusion of rhIGF-I raised serum IGF-I to about 180% of control values, and GHRH-ANT injections lowered serum IGF-I to about 33% of control. The IGF-I infusion induced an increase in left kidney weight when expressed in absolute units but not when expressed as a percentage of body weight; there was also an increase in glomerular volume in the IGF-I treated rats. GFR, single nephron GFR, and single nephron plasma flow also rose with IGF-I infusion, and these changes were associated with decreased afferent and efferent arteriolar resistance and increased glomerular ultrafiltration coefficient. GHRH-ANT injection did not affect kidney weight or glomerular volume; however, GFR, single nephron GFR, and single nephron plasma flow were reduced in association with an increase in efferent arteriolar resistance. There also was a tendency, not significant, for the glomerular ultrafiltration coefficient to decrease. The findings that a low dose of rhIGF-I, which raised the serum IGF-I only modestly, increased glomerular ultrafiltration and that reducing serum IGF-I below control values decreased glomerular dynamics suggest that physiological or pathophysiological changes in IGF-I may affect and possible help to regulate glomerular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effects of recombinant human insulin-like growth factor I on glomerular dynamics in the rat.

This study was undertaken to investigate the mechanisms by which an infusion of recombinant human insulin-like growth factor I (rhIGF-I) increases GFR and renal plasma flow (RPF) in rats. Glomerular micropuncture studies were carried out in 14 nonstarved Munich Wistar rats and in 12 rats deprived of food for 60-72 h. Animals were given an intravenous injection and infusion of either rhIGF-I or vehicle. In both nonstarved and starved animals, the IGF-I injection and infusion increased the serum IGF-I levels, left kidney GFR, single nephron glomerular filtration rate (SNGFR), single nephron blood flow rate (SNBF), and single nephron plasma flow rate (SNPF). The increase in SNPF and SNGFR was in part due to a fall in efferent arteriolar resistance (RE); there was a tendency, not significant, for afferent arteriolar resistance (RA) to fall in comparison to controls. The increase in SNGFR was partly caused by a rise in SNPF but was primarily due to an increase in glomerular ultrafiltration coefficient (LpA) to twice the control values. The increase in LpA resulted in an increase in SNGFR because the rats operated at ultrafiltration pressure disequilibrium. Control starved as compared with nonstarved rats had lower SNGFR, SNBF, and SNPF. This reduction was due to a tendency, not significant, for both RA and RE to be higher. Decreased SNGFR in food-deprived rats resulted from a reduced SNPF, a lower glomerular transcapillary hydrostatic pressure difference (delta P), and possibly a somewhat reduced LpA. These data indicate that IGF-I increases SNGFR, SNPF, and SNBF primarily by increasing LpA and also by decreasing RE without affecting delta P. Short-term starvation lowers SNGFR, SNPF, and SNBF primarily by decreasing delta P and possibly by lowering LpA and increasing RA and RE. IGF-I reverses some of the glomerular hemodynamic effects of short-term food deprivation.

Animals↗
PubMed1991

Response of insulin-like growth factor I and renal hemodynamics to a high- and low-protein diet in the rat.

An increase in plasma insulin-like growth factor I (IGF-I) levels by growth hormone injection or IGF-I infusion can raise renal plasma flow and glomerular filtration rate. However, it is not known whether a more physiological stimulus for IGF-I will also increase IGF-I in the kidney and whether the increase in renal or serum IGF-I is correlated with the increase in renal plasma flow and glomerular filtration rate. Male rats were pair fed either a high-protein (36% protein, N = 9) or a low-protein but isocaloric diet (9% protein, N = 9) for 10 to 14 days. Renal plasma flow and glomerular filtration rate were then estimated by clearance measurements, and IGF-I was measured in extracted serum, liver, renal cortical tissue, and glomeruli. Body weight gain and combined kidney weight were higher in high-protein rats as compared with low-protein animals (0.86 +/- 0.02 SEM versus 0.77 +/- 0.02 g/100 g body wt; P less than 0.05), but liver weights were not different. Serum, liver, and glomerular IGF-I levels were also higher in the high-protein rats as compared with the low-protein animals (serum, 1.12 +/- 0.03 versus 0.80 +/- 0.06 U/mL, P less than 0.05; liver, 183 +/- 17 versus 117 +/- 16 mU/g wet wt, P less than 0.05; glomeruli, 7.43 +/- 0.73 versus 4.81 +/- 0.59 mU/mg of protein, P less than 0.05). In contrast, the renal cortical IGF-I levels were not different in high-protein versus low-protein rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗