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Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are found elevated in various conditions characterized by renal growth (e.g. diabetes mellitus, hypokalemia). To test whether IGFBP-1 is a renotropic factor, IGFBP-1 was administered alone or in combination with IGF-I to Snell dwarf mice, an in vivo model without compensatory feedback effects on growth hormone (GH) secretion. In three control groups of Snell dwarf mice, placebo, GH or IGF-I was administered. Compared with placebo, kidney weight increased in all treated groups, however, with different effects on kidney morphology. Administration of IGF-I, alone or in combination with IGFBP-1, tended to increase glomerular volume, while no changes were seen in the other groups. Administration of IGFBP-1 or IGFBP-1+IGF-I both caused dilatation of the thin limbs of Henle's loop, while GH or IGF-I administration had no visible effect. Furthermore, IGF-I administration resulted in an increased mean number of nuclei per cortical area and renal weight, whereas GH, IGF-I+IGFBP-1 or IGFBP-1 caused a decreased renal nuclei number. In situ hybridization and immunohistochemistry showed specific changes of the renal IGF system expression patterns in the different groups. Particularly, IGFBP-1 administration resulted in extensive changes in the mRNA expression of the renal IGF system, whereas the other administration regimen resulted in less prominent modifications. In contrast, administration of IGFBP-1 and IGFBP-1+IGF-I resulted in identical changes in the protein expression of the renal IGF system. Our results indicate that IGFBP-1, alone or in combination with IGF-I, demonstrated effects on the renal tubular system that differ from the effects of IGF-I.
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ABSTRACT
Indirect evidence has suggested that the kidney is a major organ of clearance for osteocalcin, a circulating marker of osteoblast function. The objectives of the present study were (1) to confirm the role of the kidney in osteocalcin clearance (2) to quantify the contribution of extrarenal sites and (3) to investigate the renal mechanism(s) of osteocalcin clearance. Plasma osteocalcin levels, osteocalcin plasma clearance rate (PCR) and plasma production rate (PPR) were determined in oophorectomized (OX) and uninephrectomized oophorectomized (UOX) sheep. The osteocalcin renal extraction efficiency (REE) and the effective renal plasma flow (ERPF) were measured, and the osteocalcin renal clearance rate (RCR) was calculated.
The osteocalcin PCR was reduced significantly in UOX compared with OX sheep (2·0±0·1 (n = 9) vs 2·5±0·1 litres/h (n = 44); P < 0·0005). In UOX sheep with plasma creatinine levels ≤ 130 μmol/l, the osteocalcin REE was 9±1·3% and the osteocalcin RCR was 50–91% of osteocalcin PCR (n = 4). In UOX sheep with plasma creatinine levels in the range 100–440 μmol/l, there was a linear relationship between osteocalcin PCR and ERPF; the osteocalcin RCR was related to the osteocalcin PCR (RCR = 0·9 × PCR −0·50). Intravenous infusion of the synthetic glucocorticoid triamcinolone acetonide (TA) in UOX sheep led to marked decrements in plasma osteocalcin levels and the osteocalcin PPR, and a significant increase in the osteocalcin PCR. These changes were accompanied by a 44% increase in ERPF. During i.v. infusion of 125I-labelled osteocalcin in three UOX sheep, the urinary excretion of trichloroacetic acid-precipitable radioactivity represented 27% (range 22–31%) of the amount cleared by the kidney. Bio-Gel P6 chromatography of urine suggested the presence of intact 125I-labelled osteocalcin and at least one radiolabelled osteocalcin fragment.
These findings confirm that the kidney is the major site of osteocalcin clearance and show that extrarenal sites also make an appreciable contribution. ERPF is an important determinant of the osteocalcin PCR. Augmentation of the ERPF by TA may mediate the induction of osteocalcin clearance by this glucocorticoid. In the UOX sheep, urinary excretion of intact osteocalcin may account for up to 30% of renal osteocalcin clearance.
Journal of Endocrinology (1991) 130, 213-221
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SUMMARY
Renal function has been studied in normal human subjects over some hours after the administration of 250 mg cortisone acetate orally or of 100 mg cortisol intravenously. Increased output of potassium without elevation of plasma concentration, and retention of sodium, were observed regularly both in the course of and without a phosphate infusion. Glomerular filtration rate and renal plasma flow were sometimes markedly elevated, sometimes unaltered. When phosphate was infused in amounts sufficient to saturate tubular reabsorptive capacity, phosphate tubular maximum was often depressed by the hormones, but sometimes unaltered. At normal plasma concentrations the usual relationship between phosphate excretion and plasma concentration or filtered load was undisturbed.
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ABSTRACT
The purpose of these studies was to determine whether the responsiveness of the kidney to parathyroid hormone (PTH) and calcitonin changed with age. Experiments were performed in young (3 months old), adult (12–14 months old) and old (22–24 months old) male Fischer 344 rats fed normal diets and thyroparathyroidectomized. Parathyroid hormone was administered i.p. at 24, 12 and 2 h before death and calcitonin was given i.p. at 12 and 2 h before death. Parathyroid hormone significantly increased the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) by renal slices from young but not adult or old animals. A similar age-related decline in the capacity of PTH to raise serum 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels was also seen. Parathyroid hormone significantly decreased tubular reabsorption of phosphorus, increased concentrations of urinary cyclic AMP (cAMP) and increased serum concentrations of calcium in all age groups. In contrast, calcitonin significantly increased 1,25-(OH)2D3 production by renal slices from both young and adult animals. Calcitonin decreased serum concentrations of calcium in young but not in adult rats. These results suggest that there are maturational changes in the PTH- and cAMP-dependent pathways in the kidney but not in the calcitonin- and cAMP-independent pathways. The changes in the PTH- and cAMP-dependent pathways affect the stimulation of 1,25-(OH)2D production but not the inhibition of phosphate transport.
J. Endocr. (1987) 114, 173–178
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SUMMARY
The renal responses of the freshwater-adapted eel, Anguilla anguilla L. to arginine vasotocin ([8-arginine]-oxytocin) have been examined. The quality of the responses to the intravenously administered peptide was found to vary with the dose. Less than 0·1 ng/kg body weight reduced glomerular filtration rate, free water clearance and rate of urine production for up to 60 min. Doses greater than 1·0 ng/kg body weight induced a 'glomerular diuresis', i.e. increased rates of urine production, glomerular filtration and free water clearance for 40–60 min. Neither the diuretic nor the antidiuretic doses produce changes in urinary composition, and no obvious direct tubular actions of the peptide were found. Arterial blood pressure, measured in the dorsal aorta, increased with some of the diuretic doses, whilst the lower doses (less than 10 ng/kg body weight) had little or no cardiovascular actions. The mechanisms involved in these dose—response characteristics are discussed with particular regard to the renal function of lower vertebrates. It is suggested that arginine vasotocin plays a primary or secondary role in the modulation of 'glomerular intermittency'.
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SUMMARY
The isolated dog kidney was perfused with blood containing 1 m-u. arginine vasopressin/ml. In other experiments 40 or 50 m-u./min. were infused into three intact dogs. Antidiuretic activity was measured in renal venous blood, arterial blood, and in the urine. Renal blood flow was determined directly in the perfused dog kidney and by p-aminohippuric acid clearance in the intact dog; glomerular filtration rate was measured by either inulin or creatinine clearance.
About 38% of the hormone was extracted from the arterial blood in its passage through the kidney. Of the total amount of hormone infused, about 18% was eliminated by each kidney. The quantity of vasopressin extracted from the blood was greater than that excreted in the urine, indicating that the hormone is inactivated by the kidney. In intact dogs, the amount of hormone filtered by the kidney was less than that excreted, suggesting tubular secretion.
It was calculated that the release of endogenous arginine vasopressin induced by the stimuli of anaesthesia and surgery was between 3 and 7 m-u./min. and that approximately 15% of the endogenous hormone was excreted.
Ultrafiltration of dog plasma at three different concentrations of arginine vasopressin (30, 100 and 290 μ-u./ml.) showed that binding was reduced as the concentration was raised and that at the concentration of hormone in the experiments, less than 30% was bound.
The difficulties of relating these findings at artificially high blood concentrations to those at physiological blood concentrations of vasopressin are discussed.
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Thyroid hormones has its main role in controlling metabolism, but it can also modulate extracellular fluid Volume (ECFV) through its action on the expression and activity of Na(+) transporters. Otherwise, chloride is the main anion in the ECFV and the influence of thyroid hormones in the regulation of chloride transporters is not yet understood. In this work, we studied the effect of thyroid hormones in the expression of ClC-2, a cell Volume-, pH- and voltage-sensitive Cl(-) channel, in rat kidney. To analyze the modulation of ClC-2 gene expression by thyroid hormones, we used hypothyroid (Hypo) rats with or without thyroxine (T(4)) replacement and hyperthyroid (Hyper) rats as our experimental models. Total RNA was isolated and the expression of ClC-2 mRNA was evaluated by a ribonuclease protection assay, and/or semi-quantitative RT-PCR. Renal ClC-2 expression decreased in Hypo rats and increased in Hyper rats. In addition, semi-quantitative RT-PCR of different nephron segments showed that these changes were due exclusively to the modulation of ClC-2 mRNA expression by thyroid hormone in convoluted and straight proximal tubules. To investigate whether thyroid hormones action was direct or indirect, renal proximal tubule primary culture cells were prepared and subjected to different T(4) concentrations. ClC-2 mRNA expression was increased by T(4) in a dose-dependent fashion, as analyzed by RT-PCR. Western blotting demonstrated that ClC-2 protein expression followed the same profile of mRNA expression.
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Recent work on kidneys from hypophysectomized (hypox) rats has shown atrophy of the proximal tubules with no effects on the other parts of the nephron. We carried out experiments to determine whether the reduction of p-aminohippurate (PAH) is consistent with structural changes in the proximal tubule of hypophysectomized rats. Initial velocities of PAH uptake by renal cortical slices were found to be constant over 30 min of incubation at concentrations of PAH up to 0·5 mmol/l for both control and hypox animals. Using kinetic analysis, it was found that both maximal velocity, V max, and the Michaelis constant, K m, were reduced in hypox animals, the relative reduction being similar for both parameters. Comparison between high Na (100 mmol/l) and low Na (6 mmol/l) media indicated that in both control and hypox rats, V max was significantly lower in low Na medium than in high Na medium, whereas K m was not changed. Efflux of PAH from pre-loaded tissue also showed a reduction in hypox animals. These results may indicate that hypophysectomy alters the capacity of PAH transport in renal cortical slices by (1) reducing the effective transport area or sites, and (2) by changing carrier–substrate affinity.
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ABSTRACT
Kidneys of adult male mice are larger than those of females because of both cellular hyperplasia and hypertrophy. Administration of testosterone to adult female mice induced cellular hypertrophy but not hyperplasia, so that the weight of the kidney remained smaller than in male mice. The sexual dimorphism in kidney size is not congenital but programmed by neonatal endogenous androgens and expressed between 30 and 40 days of age. Treatment of newborn males with cyproterone acetate and of newborn females with testosterone induced female and male patterns of renal growth respectively. It appears that neonatal endogenous androgens are required to induce the characteristic cellular hyperplasia of the kidneys of male mice. Manipulation of androgen levels during neonatal and prepubertal life was found to affect the growth response of the kidney to androgens in adult male and female mice.
J. Endocr. (1987) 115, 241–246
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Previous work [White, Heinbecker & Rolf, 1942; Pickford & Ritchie, 1944] has shown that hypophysectomized dogs cannot produce a normal water diuresis. After hypophysectomy the maximum rate of urine flow in diuresis due to the ingestion of a standard volume of water is 50 % or less of the normal, and the time taken to excrete the water may be as long as 24 hr. instead of 2½–3 hr. The glomerular filtration rate (GFR), renal plasma flow (RPF) and maximum tubular excretion as measured by inulin or creatinine and diodone clearances are markedly below normal. The condition is permanent and is present whether the dog has polyuria or a normal 24 hr. urine output. At autopsy the kidneys are microscopically normal.
The object of the observations described below was to find whether the results of this work on dogs are applicable to man, i.e. whether disease of the anterior lobe of
