Insulin-like growth factor I and the kidney.
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Acromegaly↗
Biomedical subjects
M R Hammerman
Publications and source records attributed to M R Hammerman.
Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat.
The effects of administering insulin-like growth factor I (IGF-I) were examined in a model of ischemic acute tubular necrosis in rats. Injury was induced by 75 min of bilateral renal artery occlusion. Compared to rats administered vehicle, rats administered IGF-I (100 micrograms/day via continuous subcutaneous infusion) had significantly lower serum creatinine and blood urea nitrogen levels over the course of 7 days postocclusion. Glomerular filtration rate as determined by inulin clearance was examined on day 2 postocclusion and was significantly increased in IGF-I-treated animals (0.16 +/- 0.02 ml per min per 100 g of body weight) compared to vehicle-treated controls (0.08 +/- 0.02 ml per min per 100 g of body weight). The weight loss that occurred during the course of acute tubular necrosis was ameliorated by IGF-I. Mortality was reduced from 36.7% in vehicle-treated rats to 7.1% in rats administered IGF-I. Histologically, there was much less renal injury evident at day 7 postocclusion in the IGF-I-treated rats compared to vehicle-treated controls. In contrast, growth hormone (200 micrograms administered subcutaneously for 4 days) did not affect recovery of renal function or reduce mortality postreperfusion. This report demonstrates a beneficial effect of IGF-I administration in the setting of acute tubular necrosis. Several properties of IGF-I render it a pharmacological agent with excellent potential for treatment of this condition in humans.
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Growth factors and metanephrogenesis.
The formation of all organs during embryogenesis, including kidney, is dependent on the timed and sequential expression of a number of polypeptide growth factors. Synthesis and actions of one or more members of the insulin-like growth factor, epidermal growth factor/transforming growth factor-alpha, transforming growth factor-beta, platelet-derived growth factor, fibroblast growth factor, and nerve growth factor families have been characterized in the developing metanephric kidney. Studies originating from a number of laboratories have defined the localization of growth factor mRNAs, receptors and peptides, have delineated patterns of growth factor synthesis, and have established the growth factor dependency of embryonic kidney development. The results of these investigations will be summarized in this editorial review and integrated within the broader context of growth factor cellular physiology and growth factor expression in nonrenal systems.
Animals↗
Metanephric transforming growth factor-alpha is required for renal organogenesis in vitro.
The role of transforming growth factor-alpha (TGF-alpha) in metanephric development was examined. Metanephroi were removed from 13-day-old rat embryos and grown in organ culture for up to 6 days using serum-free chemically defined media. During this time the metanephroi increased in size and morphological complexity. Messenger RNA for TGF-alpha was present in the renal anlage. Immunoreactive TGF-alpha was produced by metanephroi in vitro and released into culture media. TGF-alpha of metanephric origin coeluted with recombinant human 125I-TGF-alpha after high-performance liquid chromatography of media. In contrast, epidermal growth factor was not detectable. Levels of TGF-alpha were relatively constant during 4 days in culture and averaged approximately 10(-10) M. Growth of the metanephric anlage, arborization of the ureteric bud, and tubulogenesis within the metanephric blastema were inhibited by the addition of anti-TGF-alpha antibodies to organ cultures. These data demonstrate production of TGF-alpha by developing rat metanephroi in organ culture. The peptide is necessary for growth and development in vitro. Our findings suggest a necessary role for TGF-alpha of metanephric origin as a promoter of renal organogenesis in vivo.
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Increased distal nephron EGF content and altered distribution of peptide in compensatory renal hypertrophy.
Epidermal growth factor (EGF) precursor is synthesized within kidney in the thick ascending limbs of Henle's loop and in distal tubule. Under baseline conditions EGF precursor is localized to the luminal membrane. In contrast, functional EGF receptors are present in basolateral membranes of sensitive renal cells. Immunostainable EGF is increased in contralateral kidneys following uninephrectomy of rats. To confirm this increase and determine whether the distribution of EGF changes in this setting, we measured immunostainable EGF in kidneys originating from rats 1, 2, 5, or 14 days following unilateral nephrectomy or sham surgery. There was a suggestion of an increase in immunostainable EGF in distal tubules 5 days postnephrectomy and a definite increase 14 days postnephrectomy. At 1 or 2 days postnephrectomy, and following sham surgery, immunostainable EGF was present predominantly at luminal membranes. In contrast, immunostainable EGF was present more diffusely throughout distal tubular cells at 5 and 14 days postnephrectomy and clearly localized adjacent to both luminal and antiluminal membranes in kidneys obtained 14 days postnephrectomy. EGF extractable from kidneys was increased significantly 5 and 14 days postnephrectomy. This material is the size of mature EGF. The altered localization of immunostainable peptide indicates that a redistribution of intracellular EGF accompanies increased synthesis postnephrectomy. Antiluminal EGF precursor or mature EGF present within kidney could act as a paracrine growth factor.
Adaptation, Physiological↗
Evolving role of growth factors in the renal response to acute and chronic disease.
The roles of growth factors in the pathogenesis of various forms of acute and chronic renal disease are largely putative. Nevertheless, there is a growing body of information that links specific growth factors to particular forms of renal injury. In all instances, it is supposed that such associations are not necessarily unique and that multiple cytokines probably interact to determine the pattern of injury or the regenerative response to such injury. Regeneration of tubular epithelium after acute tubular necrosis involves upregulation of the epidermal growth factor (EGF) receptor. Early studies of exogenously administered EGF indicate that the severity and duration of renal failure may be attenuated by this growth factor. Thus far, the observed responses have been limited and the role of EGF as a therapeutic agent requires more study. The mechanism of generation of tubulointerstitial injury in most forms of renal disease is difficult to understand. Early in vitro studies of growth factor production by tubular cells (in the absence of any infiltrating cells) indicate that platelet-derived growth factor produced by the medullary collecting duct is mitogenic for renal medullary fibroblasts, suggesting a paracrine growth system in this region of the kidney. Insulin-like growth factor I has also been shown to be produced by collecting duct cells. Its production is increased by EGF, and its association with certain forms of renal hypertrophy, i.e., diabetes and hypersomatotrophic states, implies its participation in the hypertrophic growth response. Platelet-derived growth factor is a potent mitogen for glomerular mesangial cells, and its production is regulated by a variety of cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Expression of insulin-like growth factor in adult and embryonic kidney.
Insulin-like growth factors (IGFs) I and II are proinsulin-like peptides. IGF I is produced in adult and embryonic kidney. It is likely that IGF I produced locally in adult kidney regulates processes of renal transport, metabolism and growth. Renal IGF I production is stimulated by growth hormone (GH) and by epidermal growth factor (EGF). The identity of additional factors that regulate IGF I gene expression in settings such as compensatory hypertrophy and diabetes mellitus is unknown. IGF I and IGF II produced in embryonic kidney promote the metanephrogenic process. The identity of factors that regulate metanephric IGF gene expression is yet to be determined.
Autoradiography↗
Renal cellular biology of growth hormone and insulin-like growth factor I.
Growth hormone (GH) and insulin-like growth factor I (IGF-I) exert a variety of actions in renal tissue. To shed light upon the renal GH-IGF I axis we have characterized the cell biology of GH and IGF I in two parts of the nephron that are targets for these peptides, proximal tubule and collecting duct. Receptors for both GH and IGF I are present in the basolateral membrane of the renal proximal tubular cell. GH activates phospholipase C and IGF I stimulates phosphorylation of its receptor at this site. Both peptides directly enhance gluconeogenesis in proximal tubule. GH stimulates IGF I gene expression in collecting duct. IGF I of collecting duct origin could act as a paracrine growth factor in other portions of the nephron. IGF I may be causative of renal hypertrophy that occurs in the settings of hypersomatotropism, unilateral nephrectomy (compensatory hypertrophy) and diabetes mellitus.
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The renal growth hormone/insulin-like growth factor I axis.
Collecting duct is a major site of insulin-like growth factor-I (IGF-I) synthesis within kidney. Production of IGF-I at this site is stimulated by growth hormone (GH). IGF-I produced in collecting duct is likely to act on glomerulus and proximal tubule via IGF-I receptors present at these locations. Renal IGF-I may be causative of the glomerular and proximal tubular hypertrophy that occurs in hypersomatotropic states, of compensatory renal hypertrophy, and of renal regeneration following acute ischemic injury.
Animals↗
Insulin-like growth factors I and II are produced in the metanephros and are required for growth and development in vitro.
The role(s) of one family of polypeptide growth factors in a developing organ system was examined. Renal anlagen (metanephroi) were surgically removed from 13-d-old rat embryos and grown in organ culture for up to 6 d. Over this period of time when placed in serum-free defined media, the metanephroi increased in size and morphologic complexity. Messenger RNAs for both insulin-like growth factors (IGFs), IGF I and IGF II, were present in the metanephroi. Immunoreactive IGF I and IGF II were produced by the renal anlagen and released into culture media. Levels were relatively constant during the 6 d in culture and averaged 3.5 X 10(-9) M IGF I and 8.3 X 10(-9) M IGF II in media removed from metanephroi after contact for 24 h. IGF binding protein activity was not detected in culture media. Growth and development of metanephroi in vitro was prevented by the addition of anti-IGF I or anti-IGF II antibodies to organ cultures. IGF II produced by metanephroi was active in an IGF II biological assay system and addition of anti-IGF II receptor antibodies to organ cultures prevented growth and development, consistent with the action of IGF II in metanephroi being mediated via the IGF II receptor. The data demonstrate production of both IGF I and IGF II by developing rat metanephroi in organ culture. Each of these peptides is necessary for growth and development of the renal anlage to take place in vitro. Our findings suggest that both IGF I and IGF II are produced within the developing metanephros in vivo and promote renal organogenesis.
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Insulin-like growth factor I gene expression in isolated rat renal collecting duct is stimulated by epidermal growth factor.
The renal collecting duct is a site of insulin-like growth factor I (IGF I) synthesis. Epidermal growth factor (EGF) is also synthesized within the kidney in the thick ascending limb of Henle's loop and the distal tubule. EGF has been shown to regulate IGF I expression in nonrenal tissues. To shed light upon a role of EGF in intrarenal regulation of IGF I gene expression, plasma membranes prepared from collecting ducts isolated from rat kidney and collecting ducts themselves were incubated in the presence and absence of recombinant human EGF (hEGF). hEGF enhanced phospholipase C activity in collecting duct plasma membranes establishing the potential for EGF signal transduction at this site. Inclusion of hEGF in suspensions of collecting ducts increased production of immunoreactive IGF I in a concentration-dependent manner. Production was stimulated significantly by addition of 10(-8) or 10(-6) M hEGF to suspensions for 2 h. Levels of IGF I mRNA in collecting ducts were increased 2.8-fold after incubation with 10(-6) M hEGF in vitro. Our findings demonstrate a direct action of hEGF to enhance collecting duct IGF I gene expression in vitro. Such enhancement is likely to reflect an effect of EGF to stimulate IGF I production in the collecting duct of the intact kidney. Since EGF is produced in kidney, our findings are consistent with intrarenal paracrine regulation of IGF I gene expression by EGF.
Animals↗
Mannose 6-phosphate-containing peptides activate phospholipase C in proximal tubular basolateral membranes from canine kidney.
To ascertain whether mannose 6-phosphate-containing peptides that bind to the insulin-like growth factor II (IGF II)/mannose 6-phosphate receptor activate phospholipase C, we determined the effect of proliferin, transforming growth factor-beta 1 (TGF-beta 1) precursor, and beta-galactosidase on production of inositol trisphosphate (Ins-P3) in basolateral membranes isolated from the renal proximal tubule of dogs. Both proliferin and TGF-beta 1 precursor stimulated Ins-P3 production in a concentration-dependent manner. Maximal production was stimulated by approximately 10(-13) M of each peptide. beta-Galactosidase had no effect on Ins-P3 generation. Neither proliferin nor TGF-beta 1 precursor potentiated IGF II-stimulated Ins-P3 production. Mannose 6-phosphate itself had no effect on Ins-P3 generation. However, mannose 6-phosphate potentiated production stimulated by 10(-11) M proliferin or 10(-11) M TGF-beta 1 precursor while inhibiting production stimulated by 10(-14) M of either peptide. Addition of anti-mannose 6-phosphate receptor antibodies to basolateral membranes abolished proliferin and TGF-beta 1 precursor-stimulated Ins-P3 generation. We conclude that, in addition to IGF II, mannose 6-phosphate-containing ligands for the IGF II/mannose 6-phosphate receptor activate basolateral membrane phospholipase C. Such activation could reflect a common mechanism for signal transduction by these peptides mediated via the IGF II/mannose 6-phosphate receptor.
Animals↗
Renal expression of IGF I in hypersomatotropic states.
We examined insulin-like growth factor I (IGF I) gene expression in kidney in two models of hypersomatotropism, rats implanted with GH3 pituitary tumors, and rats administered exogenous growth hormone (GH). Both GH3 tumor-bearing rats and rats administered GH gained weight more rapidly than control animals, and had kidneys that were larger than those of controls. Tumor-bearing rats had increased levels of circulating IGF I. Glomeruli from tumor-implanted rats were sclerotic. Immunostainable IGF I was increased in medullary collecting ducts from tumor-bearing and GH-injected rats compared with kidneys from control animals. Levels of IGF I mRNA in kidneys of rats implanted with GH3 tumors and GH-injected rats were elevated compared with levels in kidneys from controls. Our findings demonstrate enhanced renal IGF I gene expression in hypersomatotropism. Stimulation of renal IGF I synthesis by GH could be causative of changes in renal function and renal size that occur in states of GH excess such as acromegaly.
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Growth hormone stimulates IGF I gene expression in isolated rat renal collecting duct.
To determine whether growth hormone (GH) directly stimulates insulin-like growth factor I (IGF I) gene expression in renal collecting duct, plasma membranes prepared from collecting ducts isolated from rat kidney, and collecting ducts themselves were incubated in presence and absence of GH. GH enhanced phospholipase C activity in collecting duct plasma membranes establishing the potential for GH-signal transduction. Inclusion of GH in suspensions of collecting ducts increased production of immunoreactive IGF I in a time-dependent and concentration-dependent manner. Production was stimulated significantly by addition of 10(-10), 10(-8), or 10(-6) M GH to suspensions for 2 h. IGF I produced in isolated collecting ducts was released into the suspending media. Levels of IGF I mRNA in collecting ducts were increased 2.8-fold after incubation with 10(-6) M GH in vitro. IGF I of collecting duct origin was indistinguishable from recombinant human IGF I in terms of its size and receptor-binding characteristics. Our findings demonstrate a direct action of GH to enhance collecting duct IGF I gene expression in vitro. Such enhancement is likely to reflect the mechanism by which GH stimulates renal IGF I production in intact kidney.
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Effects of growth hormone and IGF-I on renal function in rats with normal and reduced renal mass.
To characterize actions of growth hormone (GH) and insulin-like growth factor ( (IGF-I) on renal function in rats with normal and reduced renal mass, we administered recombinant bovine growth hormone (bGH) or human IGF-I (hIGF-I) to normal rats or to rats that had undergone unilateral nephrectomy and two-thirds infarction of the contralateral kidney, and measured inulin and p-aminohippurate clearances over 10-17 days. Administration of either bGH (100-200 micrograms/day) or hIGF-I (200 micrograms/day) to rats with normal renal mass increased inulin and p-aminohippurate clearances compared with those measured in animals that received vehicle. Filtration fractions were not affected by either bGH or hIGF-I. Inulin clearance was decreased to approximately 17% of normal 1 day after reduction of renal mass in rats. Over the next 3 days insulin clearance increased significantly in rats with reduced renal mass that were administered vehicle. No further enhancement occurred during the next 7 days. Neither bGH nor hIGF-I affected inulin clearance in rats with reduced renal mass. We conclude that both GH and IGF-I enhance glomerular filtration rate when administered to rats with normal renal mass, but not when administered in the same quantities to rats in which renal functional mass is reduced. Glomerular filtration rate increases within 4 days of renal mass reduction independent of exogenous GH or IGF-I.
Animals↗
Mannose 6-phosphate potentiates insulin-like growth factor II-stimulated inositol trisphosphate production in proximal tubular basolateral membranes.
To ascertain whether mannose 6-phosphate affects insulin-like growth factor (IGF) II stimulation of phospholipase C activity in the basolateral membrane of the renal proximal tubular cell, we determined the effect of mannose 6-phosphate on IGF II-stimulated production of inositol trisphosphate (Ins-P3) in isolated basolateral membranes. Production of Ins-P3 measured in the presence of 10(-10), 10(-9), or 10(-8) M rat IGF II was potentiated approximately 2-fold by inclusion of 5 mM mannose 6-phosphate in incubations. Mannose 6-phosphate had no effect on Ins-P3 production in the absence of IGF II. Neither mannose 1-phosphate, mannose, glucose 6-phosphate, nor fructose 1-phosphate exerted similar potentiation. Enhancement of IGF II-stimulated Ins-P3 production required concentrations on the order of several millimolar mannose 6-phosphate. Total and specific binding of 10(-10) M 125I-IGF II to basolateral membranes was significantly increased by 5 mM mannose 6-phosphate. However, there was no significant effect on total or specific binding of 10(-9) or 10(-8) M 125I-IGF II. Our findings suggest that mannose 6-phosphate potentiates stimulation of phospholipase C by IGF II in the basolateral membrane of the renal proximal tubular cell and that potentiation is mediated via a mechanism in addition to enhanced binding of IGF II. Such potentiation could reflect a role for the mannose 6-phosphate moiety as a modulator of IGF II "signal" transmission in vivo.
Animals↗
Cytochalasin B binding to rabbit proximal tubular basolateral membranes.
Cytochalasin B binds to the Na+-independent D-glucose transporter in non-renal tissues. We have shown previously that the Na+-independent D-glucose transporter of the rabbit renal proximal tubular cell is localized exclusively in the basolateral membrane. To determine whether cytochalasin B binds to this renal transporter we measured binding of [3H]cytochalasin B to proximal tubular basolateral membranes isolated from rabbit kidneys. A steady state of binding is reached by 15 minutes at 20 degrees C over a concentration range of 0.01 to 50 microM. Non-linear regression analysis of cytochalasin B binding from 0.01 to 20 microM plotted according to Scatchard reveals two classes of binding sites with Kd 5.88 x 10(-8) M, Bmax 16.1 pmol/mg protein; and Kd 5.62 x 10(-5) M, Bmax 2816 pmol/mg protein. [3H]cytochalasin B (0.1 microM) binding to basolateral membranes is a reversible process; it is displacable by excess unlabeled cytochalasin B with a time course similar to binding of [3H]cytochalasin B. Binding of [3H]cytochalasin B is inhibited by 500 mM D-glucose (21%), 2-deoxy-D-glucose (57%) and 3-O-methyl-D-glucose (64%), but not by L-glucose. [3H]cytochalasin B binding is reduced 71% by 0.1 mM phloretin, but only 26% by 0.1 mM phlorizin. Such substrate specificity and inhibitor sensitivity are similar to those previously demonstrated in non-renal tissues by others as well as in rabbit renal proximal tubular basolateral membranes by us. Our data suggest that cytochalasin B binds to the Na+-independent D-glucose transporter or a component of the transporter in the renal proximal tubular basolateral membrane.
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Growth hormone activates phospholipase C in proximal tubular basolateral membranes from canine kidney.
To delineate pathways for "signal" transduction by growth hormone (GH) in proximal tubule, we incubated basolateral membranes isolated from canine kidney with human growth hormone (hGH) or human prolactin (hPrl) and measured levels of inositol trisphosphate (InsP3) in suspensions and of diacylglycerol extractable from the membranes. Incubation with hGH, but not hPrl, increased levels of InsP3 and diacylglycerol in a concentration-dependent manner. Half-maximal effects occurred between 0.1 and 1 nM hGH. Increased levels of InsP3 were measured after as little as 5 sec of incubation with 1 nM hGH, and increase was maximal after 15 sec. Increases were no longer detectable after 60 sec because of dephosphorylation of InsP3 in membrane suspensions. hGH did not affect rates of dephosphorylation. hGH-stimulated increases in InsP3 were detectable in membranes suspended in 0, 0.1, and 0.2 mM calcium but not in 0.3 or 1.0 microMs calcium. 125I-labeled hGH-receptor complexes with Mr values of 66,000 and 140,000 were identified in isolated basolateral membranes. Our findings establish that GH activates phospholipase C (phosphatidylcholine cholinephosphohydrolase, EC 3.1.4.3) in isolated canine renal proximal tubular basolateral membranes, potentially after binding to a specific receptor. This process could mediate "signal" transmission by GH across the plasma membrane of the proximal tubular cell and elsewhere.
Animals↗