Infused IGF-I/IGFBP-3 complex causes glomerular localization of IGF-I in the rat kidney

Alexander Sandra, Mary Boes, Brian L. Dake, John B. Stokes, and Robert S. Bar

Departments of Internal Medicine and Anatomy, Diabetes and Endocrinology Research Center, Veterans Administration Medical Center, The University of Iowa, Iowa City, Iowa 52246

    ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Insulin-like growth factor I (IGF-I) increases renal blood flow, glomerular filtration rate (GFR), and proximal tubule reabsorption of phosphate in humans and rodents. The biological effects of IGF-I are likely to be influenced by cellular localization of IGF-I within the kidney. We therefore tested whether the renal localization of infused IGF-I could be altered if given with selected IGF-binding proteins (IGFBPs). Rats were treated with intravenous injections of 125I-labeled IGF-I, 125I-IGFBP-3, or 125I-IGFBP-4 alone or with complexes of 125I-IGF-I and IGFBP-3 or IGFBP-4. The cellular localization of IGF and the IGFBP within the kidney was then determined. 125I-IGF-I, 125I-IGFBP-4, and 125I-IGF-I/IGFBP-4 complexes were found almost exclusively in vacuolar structures (endosomes) of proximal renal tubules. In contrast, about one-third of renal 125I-IGFBP-3 and 125I-IGF-I/IGFBP-3 was localized to glomeruli. When 125I-IGF-I was given alone, 3% was found in glomeruli and 89% in proximal tubules. When given as 125I-IGF-I/IGFBP-3, 29% was in glomeruli and 65% in proximal tubules. We conclude that the cellular localization of IGF-I within the kidney can be directed to glomerular elements if the IGF-I is given with IGFBP-3.

renal redistribution of insulin-like growth factors

    INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

THE INSULIN-LIKE GROWTH FACTORS (IGFs) IGF-I and IGF-II exert both metabolic and mitogenic effects in several tissues throughout the body (18, 20, 28). The IGFs are present in the highest concentration in the circulation, where >90% of IGF-I and/or -II circulates as part of a 150-kDa trimeric complex composed of IGF, IGF-binding protein (IGFBP)-3, and an acid labile subunit (5, 6). When in the 150-kDa complex, IGF is thought to be biologically inert, and the complex is largely confined to the circulation (7). At the tissue level, biological effects of IGF, whether derived from the circulation or produced by the tissue itself, are dependent on a complex interplay involving IGF, ambient IGF-binding proteins (IGFBP-1 through IGFBP-6), IGFBP protease(s), and specific IGF receptors of the target cell (4, 8, 25). Of the six high-affinity IGF-binding proteins, IGFBP-3 and specific IGFBP-3 fragments have the most diverse biological effects, causing both inhibition and potentiation of specific IGF functions while also having intrinsic biological activities independent of IGF (10, 11, 24, 25, 27).

In the intact animal, perhaps the most IGF-sensitive tissue/organ is the kidney. In both rodents and humans, treatment with relatively low doses of IGF-I causes a rapid increase in renal plasma flow and glomerular filtration rate (14-16). To gain insight into the potential influence of IGFBP-3 on IGF-mediated renal function, in the present study rats were infused with IGF-I alone, IGFBP-3 alone, or IGFBP-3 plus IGF-I, and the tissue localization within the kidney was determined by autoradiographic methods. Localization data for infused IGFBP-3 were then compared with the tissue localization data in the kidney of a second group of animals perfused with IGFBP-4 or IGFBP-4/IGF-I complexes. As previously reported by Arany et al. (2), IGFBP-3 was found throughout the kidney, with particular localization in cellular elements of the glomerulus. In contrast, IGF-I, as well as IGFBP-4, was found almost exclusively in proximal renal tubules, with striking enrichment in vacuolar structures of the tubules. When IGF-I was infused with IGFBP-3, the localization of IGF-I more closely approximated that of IGFBP-3, with an increase of IGF-I in the glomerulus and a decrease in localization within the proximal tubules. These data indicate that the kidney localization, and perhaps renal bioactivity, of infused IGF-I can be altered if the IGF-I is infused in the presence of IGFBP-3.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

IGF-I (Intergen, Purchase, NY), IGFBP-3 (a gift from Celtrix, Santa Clara, CA), and IGFBP-4 [made in Baculovirus as per protocol of Invitrogen (San Diego, CA)] were iodinated with Na125I by the lactoperoxidase method as previously described (13). Specific activities of 125I-labeled IGF-I, IGFBP-3, and IGFBP-4 ranged from 40 to 100 µCi/µg protein. Heart perfusion buffer (HPB) consisted of Hanks' balanced salt solution, pH 7.4, with glucose (1 g/l), fatty acid-poor albumin (1 mg/ml; Intergen), and 1 mM HEPES (Sigma Chemical, St. Louis, MO) in place of sodium bicarbonate.

Perfusion Studies

Sprague-Dawley rats, 250-274 g (Harlan Laboratories, Indianapolis, IN), were anesthetized with methoxyflurane (Pitman-Moore, Mundelein, IL) before tail vein injections with IGF-I and/or IGFBPs. 125I-IGF-I, 125I-IGFBP-3, and 125I-IGFBP-4 [2 × 107 counts/min (cpm) in 300 µl HPB] were each injected into the tail vein and allowed to circulate for 1 or 10 min. The chest cavity of the animal was then opened, a 19-gauge needle was inserted into the left ventricle, and 200 µl of blood were removed for analysis of degradation of the 125I-labeled protein. To clear blood from the circulation, the rat was next perfused through the ventricular needle with 100 ml of PBS, 37°C, at 130 mmHg by gravity flow. To fix tissues, the perfusate was then changed to a solution of 2.5% glutaraldehyde in 67 mM sodium phosphate, and 100 ml of the fixing solution were infused.

Rats were also treated with either IGFBP-3 and 125I-IGF-I or IGFBP-4 and IGF-I. Treatment of an animal with both IGFBP and IGF-I was done in two ways. 1) Rats were preperfused with unlabeled IGFBP by injecting 100 µg of unlabeled IGFBP (IGFBP-3 or IGFBP-4) in 300 µl HPB, a mixture that was allowed to circulate for 10 min. The rat was then given 2 × 107 cpm 125I-IGF-I in 300 µl HPB; this was allowed to circulate for 1 min, after which the kidney tissues were fixed and analyzed. 2) Rats were infused with a mixture of 125I-IGF-I (2 × 107 cpm) and unlabeled IGFBP-3 or IGFBP-4 in a 1:10 IGF-I/IGFBP molar ratio. After 1 min, the tissues were fixed and prepared for analysis.

Tissue Fixation

Light-microscopic level autoradiography. Kidneys were rapidly dissected and cleaned of perirenal fat and connective tissue. The kidneys were then cut coronally, processed by standard methods, and embedded in paraffin. Sections (8 µm) were cut, mounted on slides, deparaffinized, and coated with Kodak NTB2 nuclear track emulsion. After 1-2 wk of development, the slides were processed with D-19 developer and hypofix. The slides were stained with hematoxylin and eosin and were analyzed (as described in Analysis) for silver grain distribution with a light microscope equipped with a ×60 and a ×100 objective lens.

Electron-microscopic level autoradiography. Rats were injected as described for light-microscopic level autoradiography except that the counts per minute of the injected IGF-I or binding protein were increased 10-fold. After removal of the kidneys, representative cortical and medullary areas were dissected out and processed for electron microscopy by postfixing in osmium tetroxide, dehydration in graded ethanol, and embedding in Epoxy resin. Thin (50 nm) sections of the tissue in the areas of the glomerulus and tubules were cut, mounted on nickel grids, and covered with a monolayer of Ilford L-5 emulsion. After 2-4 wk of development, the grids were processed using Microdol-x developer. Grids were stained with lead citrate and uranyl acetate before being viewed in a Hitachi E600 electron microscope.

Analysis

Silver grains at both the light- and electron-microscopic levels were counted and analyzed for localization. For 125I-IGF-I alone, 125I-IGFBP-3 alone, and IGFBP-3 plus 125I-IGF-I, the data represent the distribution of ~60,000 silver grains counted at the light level in at least three independent experiments. An equal number of microscopic fields were randomly chosen and analyzed in each treatment group, and individual silver grains were assigned to a cellular compartment. The cellular compartment assigned was based on the localization of the grains to a distance within 0.2 µm. The density of background silver grains on the periphery of each slide was subtracted from the density over tissue sections. This background averaged 5% of the grain density associated with cells. Values are means ± SE of at least five rat kidneys. For studies with IGFBP-4, both kidneys from a single rat were analyzed.

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Rats were infused with 125I-IGF-I, 125I-IGFBP-3, or 125I-IGFBP-4. The relative distribution of radioactivity in several organs/tissue is given in Table 1. After 1-min circulation of the 125I-labeled protein, the kidneys were removed and analyzed for 125I grains at the light- and electron-microscopic levels. 125I-IGF-I was also infused 1) with IGFBP-3 or IGFBP-4 and 2) after animals had been pretreated with intravenous IGFBP-3 or IGFBP-4. Results were similar whether 125I-labeled compounds were allowed to circulate for 1 or 10 min. Data reported in Tables 1 and 2 and in Figs. 1-5 reflect 1-min circulation times for 125I-labeled compounds.

                              
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Table 1.   Distribution of infused 125I-IGFBP-3, 125I-IGFBP-4, and 125I-IGF-I

                              
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Table 2.   Distribution of infused IGF-I, IGFBP-3 and IGFBP-4 within rat kidney

IGFBP-4 and IGF-I Perfusions

At the light-microscopic level, autoradiographic grain counts demonstrated that infused 125I-IGF-I and 125I-IGFBP-4 were each localized to the proximal tubule, with a glomerulus-to-proximal tubule ratio of ~1:30 (Fig. 1, Table 2). When 125I-IGF-I was coinfused with unlabeled IGFBP-4 after IGFBP-4 pretreatment, or chemically cross-linked to IGFBP-4 (data not shown), the distribution of 125I-IGF-I within the kidney was unchanged (Table 2). With higher magnification at the light level, the majority of the silver grains for both 125I-IGF-I and 125I-IGFBP-4 appeared localized over vacuoles near the apical surface of the tubule epithelium (Fig. 2). Electron microscopy revealed that intracellular silver grains representing IGF-I or IGFBP-4 were predominantly localized to vacuolar structures, most likely early endosomes resulting from endocytotic activity (Fig. 3). After 1 and 10 min of circulation, 125I-IGF-I and 125I-IGFBP-4 in the blood were >90% intact, as judged by TCA precipitation or SDS-PAGE analysis.


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Fig. 1.   Light-microscopic level autoradiograph showing localization of 125I-labeled insulin-like growth factor-binding protein (IGFBP)-4 in rat kidney. Label is primarily found in proximal tubule epithelium (arrows). * Tubule joining a glomerulus. Bar, 10 µm.


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Fig. 2.   Light-microscopic level micrograph (with higher magnification than that shown in Fig. 1) of 125I-IGFBP-4 in rat proximal tubule. Silver grains are mostly localized in apical portion of epithelial cells. Bar, 10 µm.


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Fig. 3.   Electron-microscopic autoradiograph of 125I-IGFBP-4 in rat proximal tubule. Label is found in apical brush border (BB) and is associated with vacuolar system of kidney epithelial cell (arrows). Bar, 1 µm.

IGFBP-3

In contrast to IGFBP-4, the renal distribution of infused 125I-IGFBP-3 was shifted to the glomerulus with a glomerulus-to-proximal tubule ratio of ~2:3, i.e., 39% of the IGFBP-3 grains were in glomeruli, 57% in proximal tubules, and 3 and 1% in distal tubules and collecting ducts, respectively (Fig. 4, Table 2). Electron microscopy of the glomerulus revealed that 55% of the silver grains were associated with podocytes or podocyte processes. The remaining grains within the glomeruli were distributed between the capillary endothelium/basement membrane (30%) and mesangium (15%) (Fig. 5).


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Fig. 4.   Light-microscopic level micrograph of 125I-IGFBP-3 in rat kidney. Silver grains are localized in both proximal tubule cells (arrows) and glomerulus (arrowheads). Bar, 10 µm.


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Fig. 5.   Electron-microscopic autoradiograph of 125I-IGFBP-3 localized in glomerulus of rat kidney. Silver grains are distributed among podocytes (arrows), basement membrane (arrowheads), and mesangium cells (*). Bar, 1 µm.

125I-IGF-I was also infused in IGFBP-3-treated rats. This was done in two ways. 1) Rats were first preperfused with IGFBP-3 (100 µg injected in tail vein). The unlabeled IGFBP-3 was allowed to circulate for 10 min, and then 125I-IGF-I (2 × 107 cpm in 300 µl buffer) was injected in the tail vein and allowed to circulate for 1 min. 2) 125I-IGF-I (2 × 107 cpm) and unlabeled IGFBP in a 1:10 ratio were coinfused and allowed to circulate for 1 min. Both treatments resulted in a changed renal distribution of 125I-IGF-I (Table 1). In rats preperfused with IGFBP-3, 8% of grains were in the glomeruli and 77% were in the proximal tubule. In rats in which 125I-IGF-I was coinfused with IGFBP-3, the redistribution of 125I-IGF-I to glomerular structures was more striking, with 29% of grains localized to the glomerulus and 65% to the proximal tubule, a distribution similar to that of rats treated with 125I-IGFBP-3 alone (39% glomeruli, 57% proximal tubule) and clearly different from renal localization of 125I-IGF-I in rats treated solely with 125I-IGF-I (3% glomeruli, 89% proximal tubule). After 1 min of circulation, >90% of 125I-IGF-I and 125I-IGFBP-3 in the blood represented intact protein, as judged by TCA precipitation or SDS-PAGE analysis.

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

In the present study, 125I-IGF-I, 125I-IGFBP-4, and 125I-IGFBP-3 were infused into rats, and the distribution of the labeled proteins within the kidney was determined. In addition, the effect of each binding protein on the renal localization of infused 125I-IGF-I was also determined. Infused IGF-I, IGFBP-4, and IGFBP-4 with IGF-I were localized in endocytotic vacuoles of the proximal tubules, the major degradative pathway in the kidney. In contrast, for infused IGFBP-3, nearly 40% of the renal IGFBP-3 was retained in glomeruli, associated with podocytes, endothelium/basement membrane, and mesangial cells. Of perhaps greatest interest, the localization of infused IGF-I within the kidney was substantially altered when IGF-I was introduced after IGFBP-3 pretreatment or, more strikingly, if IGF-I and IGFBP-3 were infused together. When given as an IGF-I/IGFBP-3 coinfusion, 29% of renal IGF-I was in glomeruli vs. only 3% of IGF-I in the glomeruli when IGF-I was injected alone.

In both humans and rats, treatment with IGF-I results in a rapid increase in glomerular filtration rate (GFR), renal blood flow, and proximal tubular reabsorption of phosphate. The precise cellular mechanisms by which IGF-I mediates these effects are not entirely clear. Type 1 IGF (IGF-I) receptors, as well as the ability to synthesize IGF-I, are both properties of the three cell types of the glomerulus (endothelial, mesangial, and epithelial cells) (3, 12). In contrast, the proximal tubule has a high density of IGF-I receptors but little ability to synthesize IGF-I, whereas, in humans, the cells of the distal tubule and collecting ducts synthesize substantial IGF-I but lack specific IGF-I receptors. The mismatch of IGF-I receptors and endogenous IGF-I synthesis along the nephron has suggested the potential for autocrine, paracrine, and endocrine functions of IGF-I within the kidney (17). Furthermore, it may be reasonable to speculate that the IGF-I-induced increase in renal plasma flow and perhaps in GFR is likely mediated through the endothelial and mesangial cells of the glomerulus, whereas the increase in phosphate reabsorption is initiated through IGF-I interaction with the dense concentration of type 1 IGF receptors in the proximal tubule, the major site of phosphate reabsorption in the kidney (9).

Further impacting on the results of the present study is the finding that, in rats and perhaps humans, the kidney is the major site of degradation of injected or infused IGF-I. This occurs despite the presence of increased receptors for IGF-I in other tissues, e.g., skeletal muscle and heart, as well as the presence of enzymes capable of degrading IGF-I in most tissues of the rat. In a recent report, Tanaka et al. (30) injected rats with recombinant human IGF-I and determined localization and degradation of IGF-I in tissues 15 and 60 min after injection. The kidney was the only tissue having a higher concentration of IGF-I than plasma and accounted for 69% of the elimination of the injected IGF-I from the circulation. Therefore, it is not unreasonable to speculate that altering the localization of injected IGF-I within the kidney by giving it with IGFBP-3 could potentially alter the effects of exogenously administered IGF-I.

In recent years, several clinical trials of IGF-I therapy have suggested beneficial effects of IGF-I in disorders as diverse as growth hormone insensitivity (Laron dwarfism) (22), renal failure (26), insulin resistance syndromes and diabetes mellitus (21, 29), AIDS (23), and osteoporosis (19). In these clinical studies it was determined that the frequency and severity of side effects progressively worsened as the dose of IGF-I was increased, often limiting the amount of IGF-I that could be given. Thus, at subcutaneous IGF-I doses >160 µg · kg-1 · day-1, chronic IGF-I therapy became difficult because of side effects. In attempts to diminish IGF-I side effects while maintaining its beneficial actions, a limited number of studies have reported successfully giving IGF-I to humans as IGF-I/IGFBP-3 complexes (1). An additional rationale for giving IGF-I as a complex with IGFBP-3 is based on the finding that when IGF-I and IGFBP-3 in the circulation are present as part of the 150-kDa complex (IGFBP-3/IGF-I/acid labile subunit), the IGF-I and IGFBP-3 are largely limited to the vascular compartment, having plasma half-lives of ~16 h (2, 3, 17). However, when IGF-I is in the ~50-kDa IGF-I/IGFBP-3 complex, the complex readily traverses the capillary endothelium, having a plasma half-life of ~25 min. The findings of the present study suggest an additional potential renal benefit of combined IGF-I/IGFBP-3 therapy. When IGF-I is given in this complex, not only could higher doses of IGF-I be given to humans, but the potential diversion of IGF-I away from degradative pathways in the kidney could potentiate the renal effects of IGF-I. Studies in humans comparing the renal effects of therapy with IGF-I alone or IGF-I given as IGF-I/IGFBP-3 complex are required to corroborate or refute this speculation.

    ACKNOWLEDGEMENTS

This work was supported by research funds from the Veterans Administration and National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-25421, DK-25295, and DK-52617.

    FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests: R. S. Bar, The Univ. of Iowa, Dept. of Internal Medicine, ENDO-3E19 VA Medical Center, Iowa City, IA 52246.

Received 23 January 1998; accepted in final form 3 April 1998.

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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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Am J Physiol Endocrinol Metab 275(1):E32-E37
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society




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