hammerman ajp 1993 ghigfi revisited

The growth hormone insulin-like growth factor axis in kidney revisited

MARC R. HAMMERMAN AND STEVEN B. MILLER George M. O’Brien Kidney and Urological Disease Center, Renal Division, Departments of Internal Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis Missouri 63110

Hammerman, Marc R., and Steven B. Miller. The growth hormone insulin-like growth factor axis in kidney revisited. Am. J. Physiol. 265 (Renal Fluid Electrolyte Physiol. 34): Fl-F14,1993.-Studies characterizing actions of growth hormone (GH) and insulin-like growth factors (IGF) in kidneys of adult and developing animals and humans have provided a good deal of insight into the functions of these peptides. Although certain of the actions may be mediated directly by GH, most appear to result from effects of GH to increase levels of circulating IGF or IGF produced in kidney. In addition to GH, epidermal growth factor (EGF) enhances the renal synthesis of IGF-I. Enhancement of renal IGF-I expression is GH independent in compensatory hypertrophy. Stimulation of kidney IGF-I production also occurs in diabetes mellitus. Renal IGF-I production is elevated in these settings in the absence of changes in circulating IGF-I, consistent with a causative role of renal IGF-I for the accompanying increased glomerular filtration rate and kidney growth. Actions of IGF in kidney are initiated following binding of peptides to specific receptors. Receptor number may be altered during compensatory growth and in diabetes mellitus. In addition to IGF, several IGF binding proteins (IGFBP) are produced in kidney and are likely to both inhibit and enhance the actions of IGF in different circumstances through sequestration of peptides and regulation of peptide interactions with their receptors. Administration of IGF-I to rats following acute ischemic injury hastens the recovery of normal renal function and accelerates the regeneration of the damaged proximal tubular epithelium. IGF-I increases the glomerular filtration rate in humans with normal and reduced functional kidney mass. These findings establish the potential for use of this peptide as a therapeutic agent in the settings of acute and chronic renal failure. acute renal failure; chronic renal failure; compensatory hypertrophy; diabetes mellitus; epidermal growth factor; mesonephros; metanephros; remnant kidney

WE PUBLISHED AN EDITORIAL REVIEW on the kidney settings of hypersomatotropism and compensatory hy- growth hormone (GH)-insulin-like growth factor (IGF) pertrophy, but in diabetes mellitus. The participation of axis in 1989 (42). That review summarized what was IGF-I and IGF-II as growth factors for the metanephric known at that time concerning the roles of GH and IGF kidney is indicated by experiments describing the ex- as regulators of renal function, growth, and development pressions of these growth factors during renal embryo- and relating to the synthesis of IGF within renal tissue. During the years since 1989 a good deal of additional

genesis and the adverse consequences of blocking their activities. Compelling evidence for a role for IGF-I pro-

information about the renal GH-IGF axis has been produced in the embryonic mesonephros as an inducer of vided by a number of laboratories. For example, much limb development has been presented. A role for IGF-I has been learned about the regulation of IGF-I and of IGF-I receptor expression within kidney. The synthesis

as a therapeutic agent in the setting of acute ischemic

of multiple IGF binding proteins (IGFBP) has been de- renal failure has been suggested by its ability to enhance

scribed in renal tissue, and roles for one or more of these recovery of renal function and normal renal histology in rats with experimental acute tubular necrosis. IGF-I has

agents as modulators of kidney IGF activity have been been safely administered to humans with normal and proposed. Evidence has been presented that IGF produced in kidney may be causative of the changes in renal

reduced renal function, and increases in glomerular filtration rate and renal plasma flow have been recorded.

function and morphology that occur not only in the The observations outlined above represent only a por- 0363-6127/93 $2.00 Copyright 0 1993 the American Physiological Society Fl

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tion of what has been learned about the GH-IGF axis in kidney since 1989. Clearly the topic has been the focus of attention not on ly in many laboratories that are concerned wi th renal physiology, but also in laborato ries that have maintained a traditional focus outside of the kidney. Considering the volume of new data and the diverse sources of information, the level of agreement among observations made by most investigators is quite high. However, discordance exists among certain findings, some of which can be reconciled and some of which cannot. For example, controversies have arisen relating to the sites of IGF synthesis and binding within kidney, relating to the roles tha tIGFp lay in normal renal physiology and as causative agents for pathophysiology, and relating to the potential usefulness of GH and IGF-I as therapeutic agents in the setting of renal failure.

The purpose of this editorial review is to revisit the GH-IGF axis in kidney. Several very complete summa- ries of the literature relating to IGF and kidney have recently been published (53, 61, 81, 82, 110). Therefore, the present review will not be encyclopedic. Rather, its purpose is threefold: 1) to summarize some of the information generated since 1989 relating to discreet aspects of the GH-IGF axis in kidney and to analyze it within the context of what was known at that time, 2) to iden- tify areas of disagreement within the literature a nd to attempt to resolve apparently conflicting observations when possible, and 3) to suggest di rections for future investigations. Since much more is known about the synthesis and actions of IGF-I in kidney than about IGF-II, the bulk of the review will focus on IGF-I.

IGF-I SYNTHESIS IN KIDNEY

IGF-I is a proinsulin-like peptide, 70 amino acids in length (42, 93). Whereas its production in liver supports predominantly an endocrine function, production in ex- trahepatic tissues such as kidney supports both autocrine and paracrine functions and is regulated differently. The rat IGF-I gene spans -100 kilobases and consists of at least 6 exons (93). Exons 1 and 2 encod .e altern .ate leader sequences including 5’ untranslated regions an .d the amino terminals of signal peptides. Exons 3 and 4 contain the mature IGF-I peptide-coding sequence. Exon 5 and part of exon 6 encode alternate E domains that are cleaved posttranslationally in mature IGF-I. The bulk of exon 6 contains the 3’ untranslated region. Use of alternative promoters acting on multiple initiation sites, differential RNA splicing, and variable RNA polyadenyla- tion are responsible for the production of multiple IGF-I mRNA species in mammals and ultimately IGF-IA and IGF-IB proteins that differ in their E domains (93). In rat liver, transcription initiation occurs at four distinct sites in exon 1 of the IGF-I gene and at a cluster of sites in exon 2. Exon 2 transcripts appear later in postnatal development than do exon 1 transcripts coincident with the appearance of circulating IGF-I. Exon 1 transcripts are present in all tissues, where they show moderate GH dependence. Exon 2 transcripts are expressed in liver, testis, lung, stomach, and kidney. They appear to be more GH-dependent in liver than in nonhepatic tissues. The usage of transcription start sites is altered in kidney dur-

ing postnatal development. Within exon 1, start site 3 is expressed constitutively throughout perinatal and postnatal development, whereas usage o f start site 2 is not detected until weaning. In addition, exon 2 transcripts do not appear in kidney until the postnatal period. The different mRNAs produced at different times during development in kidney through the use of alternative start sites may reflect differential regulation of IGF-I production for autocrine or paracrine function (97).

Most of the studies characterizing IGF-I synthesis within kidney have utilized animal models, usually rat. Rat renal IGF-I has full biological activity (40). It is clear that its expression in rat kidney is regulated not only by GH, but by a number of factors in addition (see below). Recently, Chin and Bondy (19) have suggested that IGF-I is not synthesized in adult human kidney and that, therefore, the autocrine/paracrine/endocrine roles of IGF-I are quite different in rat and human renal tissue. This suggestion was based on the inability of the au- thors to detect IGF-I mRNA in adult human kidney by in situ hybridization using a human cRNA probe. In contrast, IGF-I mRNA was found in rat kidney using a rat cRNA probe (19).

The observation that IGF-I mRNA is absent from human kidney is somewhat unexpected in light of several findings. Han et al. (46) and Hill et al. (50) localized immunoreactive IGF-I to human fetal kidney and Han et al. (47) detected IGF-I mRNA in human fetal kidney using Northern analysis. Bell et al. (13) detected mRNAs for both IGF-I and IGF-II in adult human kidney. Aron et al. (5) described the presence of IGF-I mRNA in glomerular mesangial cells cultured from human kidney and documented synthesis of IGF-I in vitro.

It is of obvious importance to determine whether adult human kidney is or is not a site of IGF-I synthesis in terms of defining our ability to extrapolate data generated in rats to humans. Therefore, we obtained RNA from adult human kidney and liver and probed for IGF-I mRNA using a highly sensitive and specific solution- hybridization nuclease-protection assay that we have used in previous investigations (15). The assay for human IGF-I mRNA utilized a 32P-labeled antisense cDNA probe designed to protect 182 nucleotides within exon 4. As shown in Fig. 1, we were able to detect IGF-I mRNA in adult human kidney. There is approximately as much IGF-I mRNA extractable from human whole kidney relative to human whole liver as is present in rat whole kidney relative to rat whole liver (15).

We believe that the data shown in Fig. 1 interpreted within the context of the finding of IGF-I mRNA in human kidney by others led to only one conclusion. There can be no doubt that adult human kidney has the capacity to synthesize IGF-I. The autocrine/paracrine/endocrine roles of this peptide are likely to be similar in rat and in human renal tissue.

Studies utilizing immunohistochemistry have localized IGF-I to cortical and medullary collecting duct, the thin limb of Henle’s loop and the distal convoluted tubule (4, 15,48,59). Studies designed to detect IGF-I mRNA using in situ hybridization have generated somewhat conflicting results. Matejka et al. (66) found IGF-I mRNA to be

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Human Human Liver Y Kidney

s A * * ‘ib i? i

-182 nt

Fig. 1. Autoradiogram depicting the result of a solution-hybridization nuclease- protection experiment using a 32P-labeled human insulin-like growth factor I (IGF-I) exon 4 antisense probe [protected fragment = 182 nucleotides (nt)]. These protected fragments originated from RNA extracted from whole human liver and whole human kidney. Y, yeast tRNA.

localized in medullary collecting ducts and sparsely in cortical collecting duct cells of rat kidney. In addition, IGF-I mRNA was expressed in scattered proximal tubular cells in the cortex and in cells confined to the glomerular tuft. In contrast, Chin et al. (20) found IGF-I mRNA to be localized in the epithelial cells of medullary thick ascending limbs of Henle’s loop. Using a solution-hybridization nuclease-protection assay, we detected relatively large quantities IGF-I mRNA in medullary collecting ducts isolated from rat kidney (-25% of the level in whole rat liver) and lesser quantities in proximal tubules and glomeruli. In our studies, the distribution of IGF-I mRNA corresponded to the distribution of immunostainable IGF-I peptide (15).

IGF-I is produced at multiple sites in the kidney. The collecting duct is a major source of renal IGF-I production. The evidence that this is the case, in addition to that summarized above, is that collecting ducts freshly isolated from rat kidney produce IGF-I in a GH-dependent manner in vitro (89) and that collecting duct cells cultured from rabbit kidney secrete immunoreactive IGF-I into their media (6). As noted above, IGF-I is produced by human mesangial cells in culture (5). It is also produced by mesangial cells from rat (22) consistent with a glomerular origin of the peptide. Following acute ischemic injury to rat kidneys, immunostainable IGF-I (3) and IGF-I mRNA (68) can be detected in cells located in the region of the proximal tubule, suggesting that under these conditions IGF-I is expressed in this location. The identity of the cells is undetermined. It is possible that they are dedifferentiated proximal tubular cells or are stem cells activated by the ischemic injury or they may be nonprox- imal tubular cells that migrate into the area of injury. Finally, the presence of IGF-I mRNA in the medullary thick ascending limb of Henle’s loop in the rat and human nephron suggests that IGF-I is produced here in addition (19, 20).

The synthesis of IGF-I in renal collecting duct is stimulated directly by GH (89) and by epidermal growth factor (EGF) (91). The effect of EGF to enhance IGF-I synthesis was originally described in fibroblasts (21) and has been reported recently in liver (11). The fact that kidney is a major site of EGF synthesis (29) establishes the potential for an EGF-IGF-I axis within this organ.

Expressions of EGF and IGF-I in rat kidney are both enhanced in the setting of compensatory renal growth (4, 58, 62, 71) (see below). It is possible, although unproven, that renal EGF induces renal IGF-I expression in this setting.

In addition to compensatory hypertrophy, synthesis of IGF-I in kidney is enhanced in experimental diabetes mellitus (see below) and synthesis is increased in normal- appearing tissue adjacent to infarcted kidney (90). The identity of stimuli that promote IGF-I expression under these circumstances is unknown. GH may play a role to enhance renal IGF-I production in diabetes (see below). However, the enhancement postinfarction cannot be explained by the presence of a circulating factor, because kidneys contralateral to infarcted kidneys do not exhibit increased IGF-I synthesis (90).

Levels of IGF-I mRNA in rat kidney are decreased following 48 h of fasting. The decrease cannot be explained entirely on the basis of reduced circulating GH (63). Caloric restriction prevents the increase in renal cortical collecting duct IGF-I content that is observed 2 wk after five-sixths nephrectomy of rats fed ad libitum 03%

Hypersomatotropism (81), compensatory hypertrophy (27), and diabetes mellitus (96) are all accompanied by increases in the glomerular filtration rate. In addition, each of these conditions is characterized by growth of glomeruli and proximal convoluted tubules, structures known to have IGF-I receptors (see below). Unlike the case in hypersomatotropism in which levels of circulating IGF-I are increased in addition to renal IGF-I (81), elevated levels of renal IGF-I in diabetes mellitus (96) and compensatory hypertrophy (26, 62, 99) occur in the absence of changes in circulating peptide. The temporal relationship between increases in levels of IGF-I in kidney and the changes in glomerular filtration rate and renal size is an area of controversy. Some investigators demonstrate that the timing of alterations of renal IGF-I is such that it can explain the enhancements of renal growth and glomerular filtration rate. Other studies show that the changes in renal size and glomerular filtration are initiated prior to alterations in IGF-I synthesis (see below). Nonetheless, it is possible that renal IGF-I is causative, at least in part, of the changes. In an effort to

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address this question directly, Matejka and Jennische (67) compared effects of IGF-I infused directly into renal parenchyma for 7 days through an implanted catheter traversing the kidney, with actions of larger quantities of IGF-I infused directly into kidneys via the suprarenal- renal artery. Of interest, IGF-I infused directly into the renal parenchyma resulted in an increase in kidney weight, morphological alterations in the cortical distal tubules, and hyperplasia of distal tubules and the medullary thick ascending limb of Henle’s loop. In contrast, no growth response or morphological alterations were observed when IGF-I was infused intra-arterially (67). While clearly nonphysiological, these studies do provide evidence that IGF-I produced in kidney and released in kidney may be a more potent renotropic agent than is IGF-I that reaches the kidney via the circulation.

IGFBP SYNTHESIS IN KIDNEY

Virtually all IGF in circulation are in tight noncovalent association with specific binding proteins (IGFBP). This topic has been the subject of several recent reviews (1,12, 95). The coexpression of IGF and IGFBP in a number of tissues suggests that the IGF-IGFBP interaction plays an important role to modulate autocrine and paracrine actions of locally produced IGF as well as endocrine functions of circulating IGF. To date, six IGFBP (IGFBP-1 to IGFBP-6) have been cloned (9, 12, 98). In vitro, one or more IGFBP have been shown to both inhibit and enhance the actions of IGF, consistent with complex roles for these peptides in the regulation of IGF activity in vivo. Because the affinity of IGF for their binding proteins in vitro is higher under some circumstances than the affinity of IGF for their receptors, and the IGF- IGFBP complexes do not appear to bind to IGF receptors, it has been suggested that the IGFBP serve to func- tionally inactivate IGF through sequestration. This is undoubtedly true for circulating IGFBP and explains why IGF-I, which circulates at a concentration two to three orders of magnitude higher than insulin and has -6% of the hypoglycemic potency of insulin, does not induce hy- poglycemia in everyone. Conceivably, IGFBP that have bound IGF could release the IGF at selected sites of action and through this mechanism exert control over their biological functions.

IGFBP produced within a given tissue may serve to keep IGF within tissue compartments, thereby increasing their local bioavailability (1, 12, 95). IGFBP-1 and -2 contain arginine-glycine-aspartic acid (RGD) sequences near their carboxy terminus consistent with their ability to bind to cell-surface membrane integrin receptors (9, 94). In this location they could serve to position IGF near the IGF receptor and either inhibit or enhance the access of IGF to their receptors or regulate the signal-transduc- ing potency of IGF.

IGFBP-1 mRNA has been detected in the medullary thick ascending limbs of Henle’s loop and in the straight portion of cortical distal tubules in adult rat kidney by means of in situ hybridization (20). Immunohistochem- istry revealed IGFBP-1 to be localized predominantly in papillary collecting ducts with moderate staining in the cortical collecting ducts and medullary thick ascending

limbs of Henle’s loop (59). IGFBP-1 (78) and IGFBP-2 (17, 78) mRNAs are present in fetal rat kidney. In fetal human kidney, IGFBP-1 mRNA has been localized by in situ hybridization to epithelial cells of the collecting ducts as well as to the cells of developing glomeruli and the subcapsular metanephric blastema. IGFBP-1 protein was detected by immunoperoxidase staining around small blood vessels, in epithelial cells of collecting ducts, and in stromal connective tissue (100). The relative abundance of IGFBP-2 mRNA is eightfold higher than that of IGFBP-1 mRNA in fetal rat kidney (78). Expression of IGFBP-2 mRNA is reduced in kidney from adult rats relative to expression in fetal rats (17, 79). Chin and Bondy (19) localized IGFBP-2 mRNA to glomeruli of both adult rat and human kidneys, to the medullary in- terstitium of rat kidneys and to the epithelium of the distal nephron and collecting ducts of human kidneys. IGFBP-3 mRNA is present in adult rat kidney (2). Liver is the major source for circulating IGFBP-3. Synthesis of this binding protein in liver is GH dependent (2,95). It is of interest that, in rat, levels of IGFBP-3 mRNA are higher in kidney than in liver and that the production of renal IGFBP-3 is not enhanced by GH in hypophysectomized rats. The divergent responses of renal and hepatic IGFBP-3 gene expression to hypophysectomy and GH replacement indicate that this gene, like the gene for IGF-I, is under tissue-specific regulation (2). Of interest, the expression of IGFBP-3 mRNA in human renal carcinomas is higher than in adjacent normal kidney tissue (51). The abundance of IGFBP-5 mRNA is greater in rat kidney than in any other tissue in which it was measured (98)

Flyvbjerg et al. (34) have reported recently that a transient increase in a 30-kDa IGFBP and a 38- to 47-kDa IGFBP accompanies the renal growth early following induction of diabetes mellitus in rats. Treatment of rats with insulin abolishes the changes in IGFBP and prevents the renal growth.

IGF RECEPTORS IN KIDNEY

The distribution of IGF-I and IGF-II receptor mRNAs has been mapped in rat and human kidney using in situ hybridization. In both species each IGF receptor mRNA was found to be abundant in the tubular epithelium of the medulla and barely detectable in proximal tubules. IGF-I receptor mRNA was present in glomeruli (19). Binding of lz51-IGF-I in rat kidney was found to be widely distrib- uted throughout the entire kidney. Specific binding was highest in the inner medulla (68). We (42,44) and others (85) have reported previously that 1251-IGF-I can be cross-linked to the a-subunit of its receptor in glomeruli (85) and proximal tubules (42, 44, 85) from rat kidney. We have shown that the site of binding in the proximal tubule of rat and dog is the basolateral membrane of the renal proximal tubular cell (42, 44). Subsequent descrip- tions of IGF-I enhancement of gluconeogenesis (a metabolic process restricted to proximal tubule) in proximal tubule suspensions from dog kidney (Fig. 2) (88) and of IGF-I stimulation of Na+-dependent phosphate transport in isolated perfused proximal convoluted tubules from rabbit kidney (87) provide compelling evidence for

EDITORIAL REVIEW F5

may be causative of the growth and hyperfiltration of the diabetic kidney (80, 96). In the last several years a good

T.‘l T TIT \ deal of attention has focused on the potential role of both

GH and IGF-I in this setting. \

1,

No consistent pattern of elevation or decrease in levels of circulating IGF-I has been found in type 1 human diabetics (82). In contrast, several groups of investigators have detected an increase of kidney IGF-I in diabetic rats. Flyvbjerg et al. (36) reported a 77% increase in kid-

16” 1P KY9 a8 1c7 ney IGF-I that was maximal at 48 h postinduction of

[IGmM) disease and appeared to precede the increase in kidney

. . n. . . .a . . . size. Levels of IGF-I in kidney decreased to baseline by 4 Fig. 2. Production of glucose m suspensions ot isolated canme proximal tubules incubated in absence of IGF-I (0) or in presence of varying concentrations of IGF-I for 120 min. Data are means k SE of 6 experiments. Reprinted from Rogers et al. (88).

the presence of IGF-I receptors in the renal proximal tubule.

Several groups of investigators have examined IGF-I receptor content and IGF-I binding in kidneys of diabetic rats (see Diabetes mellitus below). Werner et al. (108) found a 2.5-fold increase in renal IGF-I receptor mRNA accompanied by a 2.3-fold increase in IGF-I binding 2 wk after the induction of experimental diabetes. They spec- ulated that increased expression of the IGF-I receptor with consequent increased IGF-I binding may play a role in the pathogenesis of diabetic nephropathy. However, Marshall et al. (64) report conflicting results. They observed a transient decrease in IGF-I binding in the first 24 h after the induction of diabetes mellitus, which was followed by a return to control values 7 days after the induction of disease. Animals that received insulin therapy, which prevented the renal hypertrophy, manifest an increase in IGF-I binding. IGF-I receptor mRNA was not measured in this study. However, Catanese et al. (18) did measure IGF-I receptor mRNA postinduction of diabetes in rats and found small decreases in IGF-I receptor mRNA at times when IGF-I mRNA was maximally increased (see below).

It has been demonstrated that IGF-I and IGF-II receptor mRNA levels increase three- to fourfold in remaining kidneys after unilateral nephrectomy in immature rats but not in adult rats (75). An increase in the specific binding of IGF-I and IGF-II to cortical membrane prep- arations appears to parallel this increase in IGF-I receptor mRNA. Levels of IGF-I receptor mRNA in kidney and binding of 1251-IGF-I to renal membranes are enhanced following 48 h of fasting (63).

EXPRESSION OF IGF IN PATHOPHYSIOLOGICAL STATES

Diabetes mellitus. Early type 1 diabetes mellitus in humans and streptozotocin-induced diabetes in rats are accompanied by renal growth and by an increase in the glomerular filtration rate. In rats, the growth can be explained by both hypertrophy and hyperplasia of proximal and distal tubules and hypertrophy of glomeruli (96). The exact etiology of the increased k idney mass and the increased glomerular fil tration rate is unknown . The observation that mean serum concentrations of GH are increased in type 1 human diabetics compared with nondiabetics has prompted the proposal that GH excess

days postinjection of streptozotocin. Diabetic rats treated with insulin had no increase in renal size or in kidney IGF-I content. Treatment of diabetic rats with octreotide, a long-acting somatostatin analogue, inhibited renal IGF-I expression and prevented hypertrophy despite the fact that glucose control was not affected (32, 35). Octreotide inhibits GH stimulation in levels of both circulating IGF-I and renal IGF-I in hypophysectomized rats (33).

Bach and Jerums (8) reported increases similar to those described by Flyvbjerg et al. (36) in renal IGF-I and also noted that while postpubertal diabetic rats manifest markedly increased kidney IGF-I at 48 h postinduction of diabetes mellitus, prepubertal diabetic rats had no such increase despite some elevation of kidney weight by day 7.

Flyvbjerg et al. (30) reported that the increase in kidney IGF-I levels 48 h postinduction of diabetes mellitus was not accompanied by a change in levels of IGF-I mRNA. They concluded that the increases in renal IGF-I might be attributed to translational regulation, trapping of circulating IGF-I, or to renal sequestration and decreased breakdown of the peptide (30). In contrast, Bach et al. (10) reported that levels of IGF-I mRNA do increase in postpubertal diabetic rats concomitant with elevations of extractable IGF-I peptide. The increase in renal IGF-I mRNA was confirmed by Catanese et al. (18) who demonstrated enhanced expression within 24 h of the onset of diabetes in rats administered 120 or 175 mg/kg streptozotocin. Levels fell to baseline by 72 h. The increase in renal IGF-I mRNA content was not observed in fasted rats. In fact, a decrease of renal IGF-I mRNA content was observed in fasted rats administered 175 mg/kg streptozotocin. Of interest, administration of 65 mg/kg streptozotocin also resulted in a decrease of IGF-I mRNA in kidney. Levels of IGF-I mRNA were reduced by insulin treatment of diabetic rats. In marked contrast to kidney, levels of IGF-I mRNA in liver were reduced in streptozotocin-induced diabetes and increased toward normal by insulin treatment. Since IGF-I mRNA levels change in opposite directions in liver and kidney, gene expression is clearly regulated in an organ-specific manner in streptozotocin-induced diabetes. Levels of lung IGF-I mRNA were unaffected by experimental manipulations (18).

The findings summarized above are difficult to reconcile, but they appear to show that the regulation of IGF-I expression in kidney following induction of diabetes mellitus in rats is influenced in a complex way by the dura- tion and severity of the metabolic abnormalities that accompany the diabetic state.

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No single stimulus for enhanced renal IGF-I expression in diabetes has been identified. Levels of circulating GH are reduced in streptozotocin-diabetic rats (14, 101). Therefore, it was concluded that GH plays little if any role to regulate renal IGF-I expression in streptozotocin diabetes (96). However, Flyvbjerg et al. (31) have shown recently that GH-deficient diabetic dwarf rats manifest attenuated renal IGF-I accumulation, have a diminished increase in glomerular volume, and a slower and lesser degree of kidney enlargement compared with pituitary- intact diabetic animals. Administration of GH to dwarf diabetic rats restored partially the renal hypertrophy, restored fully the glomerular hypertrophy, but had no effect on levels of circulating IGF-I or IGF-I in kidney. These findings indicate that the changes in kidney size and renal function that occur in diabetes may be mediated by both GH and IGF-I and that some of the GH effects are IGF-I independent (31). GH does exert other actions on renal cells that cannot be attributed to IGF-I. For example, we have demonstrated that GH stimulates gluconeogenesis in canine proximal tubular segments via a direct interaction with the cells (88).

The relationship between changes in kidney size and glomerular filtration that occur early following the onset of type 1 diabetes mellitus in humans and streptozotocin- diabetic rats and the development of diabetic nephropathy remains a speculative one. Since many years separate the onset of diabetes mellitus in humans and the development of nephropathy, the analysis of streptozotocin- induced diabetes in the rat, a relatively short-lived species, has limited applicability. On the other hand, streptozotocin-induced diabetes does provide a good model for human disease in some ways. In contrast to most forms of renal disease in which destruction of nephrons is associated with progressive renal atrophy, hypertrophy persists in longstanding human diabetes even with concomitant reduction of the glomerular filtration rate and development of microalbuminuria. It is clear, therefore, that important changes in growth control exist in the diabetic kidney which may be related to the pathogenesis of the disease state itself (96). These changes are amenable to study in the rat.

In humans, development of microalbuminuria presages diabetic nephropathy (73). It is of interest that 6 mo of treatment of diabetic rats with octreotide reduces albu- minuria, renal hypertrophy, and levels of circulating IGF-I and kidney IGF-I without affecting metabolic control of diabetes or renal function. It was suggested that the reduction of kidney size and urinary albumin excretion could result from reduced renal IGF-I expression or levels of circulating IGF-I. However, against this inter- pretation of the data is the observation that levels of circulating IGF-I and renal IGF-I are no different in non- diabetic control rats and diabetic rats that did not receive octreotide 6 mo following induction of disease (35). Ad- ministration of octreotide to humans with type 1 diabetes mellitus as well as to nondiabetics acutely reduces the glomerular filtration rate and renal plasma flow (84,106).

Compensatory hypertrophy. Both in humans and in experimental animals, removal of a single kidney results in

hypertrophy and hyperfunction of the remaining kidney. In experimental animals an increase in kidney weight and glomerular filtration rate can be detected within 24-48 h following unilateral nephrectomy (27).

Extensive literature has documented that in the adult animal the bulk of the compensatory renal growth is sec- ondary to cell hypertrophy, predominantly of the glom- erulus and proximal tubule. However, in the immature animal, hyperplasia appears to predominate, suggesting that at least two different processes mediate compensatory renal growth. Removal of increasing amounts of renal tissue in adult animals may also stimulate a more hyperplastic renal growth response (27).

The possibility that compensatory renal growth is mediated by a specific humoral renal growth factor has been a subject of investigation for decades. It has been shown that hypophysectomy decreases renal growth following unilateral nephrectomy (27, 81). Given the relationship between GH and IGF-I, attention was directed to the potential role of IGF-I in compensatory renal growth.

Stiles et al. (99) found that, although serum IGF-I levels did not change following uninephrectomy in the rat, renal tissue levels of IGF-I increased twofold 5 days after uninephrectomy, but not at 2 days, with a return to baseline by 30 days postprocedure. In addition, they found that in the hypophysectomized rat the percent increase of IGF-I content of the remaining kidney was similar to that in the pituitary-intact animal, although a concomitant increase in kidney weight was not demonstrated. They reasoned that IGF-I plays an important paracrine role in compensatory renal growth that is, at least in part, GH independent (99). Although controversy exists regarding the timing of the changes in IGF-I content postnephrectomy, these observations have been confirmed by several other groups (4,26,36,62). We (62) and Andersson et al. (4) reported increased levels of immunostainable IGF-I in medullary collecting ducts of kidneys obtained 5-14 days, but not 1 or 2 days, postnephrectomy. In contrast, Flyv- bjerg et al. (36) have reported that the increase in IGF-I is maximal 24-48 h after uninephrectomy. These investigators also showed that serum IGF-I levels were actually decreased in the uninephrectomized rat and that the administration of a somatostatin analogue prevented both the compensatory renal growth and the increase in kidney IGF-I (32).

Fagin and Melmed (26) showed that IGF-I mRNA in the remaining kidney increased five- to sixfold within 24 h of uninephrectomy. On the other hand, two subsequent studies using the solution-hybridization assay found no change in IGF-I mRNA in the adult rat kidney (62, 74) but, instead, a pronounced increase in kidney IGF-I mRNA following uninephrectomy in immature animals (74). This would suggest an age-dependent difference in the mechanism whereby compensatory renal growth takes place. Of note, the animals used by Fagin and Melmed (26) were 4-5 wk old, which is essentially within the age range of the immature animals used in the other studies.

Mulroney et al. (75) have shown that pulsatile GH

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secretion is markedly elevated 24 h after unilateral nephrectomy in adult rats compared with sham-operated control animals. The enhanced release of GH in adult rats begins to decline by 48 h postnephrectomy. An antagonist to GH-releasing factor significantly suppressed the increase in GH release after unilateral nephrectomy and attenuated the compensatory hypertrophy (75). These findings are consistent with a role for GH in early compensatory renal growth in adult rats. However, it is difficult to reconcile these observations and the findings from this laboratory (74) and our laboratory (62) that levels of IGF-I mRNA do not change in remaining kidneys postunilateral nephrectomy of adult rats, with the known rapid effect of GH to increase levels of renal IGF-I mRNA (89).

In contrast to the case in adult rats, no increase in GH secretion is observed postunilateral nephrectomy of immature rats. Administration of a GH-releasing factor antagonist to uninephrectomized immature rats inhibits somatic growth, but does not attenuate compensatory renal growth or the increase in IGF-I mRNA and IGF-I receptor mRNA observed postnephrectomy in remaining kidneys. Therefore, the initial phase of compensatory hyper-

trophy in immature rats appears to be GH independent as does the enhancement of renal IGF-I and IGF-I receptor gene expression (75).

IGF AND NEPHROGENESIS

Several polypeptide growth factors have been identified as regulatory agents for the development of the kidney. This topic, as well as the topic of participation of the Wilms’ tumor gene product in the regulation of metanephric growth factor expression has been recently re- viewed (7, 45) and will not be discussed in detail.

A role for IGF-I and IGF-II in the developing metanephros has been established. IGF-I and IGF-II mRNA can be detected in the embryonic rat kidney. When metanephroi from fetal rats are placed in organ culture, immunoreactive IGF-I and IGF-II are produced and released into the media. When anti-IGF-I, anti-IGF-II, or anti-IGF-II receptor antibodies are added to the culture media, the growth and development of rat metanephroi is prevented, consistent with a necessary role for both IGF-I and IGF-II in renal organogenesis (92) (Fig. 3).

Wilms’ tumor tissue expresses high levels of IGF-II. WTl, the product of a gene located on chromosome 11~13

Fig. 3. Photomicrographs of rat metanephroi. Shown are metanephroi cultured for 4 days in serum-free chemically defined media (control, C) or in media to which the following additions were made: mouse ascites fluid

, (AF), normal rabbit serum (S), anti-IGF-I antibodies (aIGF-I), anti-IGF-II antibodies (aIGF-II), or anti-IGF-II receptor antibodies (aIGF-IIR). Reproduced from Rogers et al., - J. Cell Biol. 113: 1447-1453, 1991; by copyright permission of the Rockefeller Univer-

, I a* .a sity Press (92). c t .I

“a

0.6 mm

F8 EDITORIAL REVIEW

that is deleted in Wilms’ tumor, codes for a zinc-finger protein that has been shown to effect transcriptional sup- pression of IGF-II (24).

It has been shown in developing chick embryos that damage to the mesonephric kidney results in truncated limbs (38). In limb bud organ cultures, the presence of the mesonephros promotes cartilage formation. This effect can be reproduced by exogenous IGF-I and prevented by anti-IGF-I antibodies (39). Both IGF-I and IGF-I receptor mRNA can be detected in the mesonephros beginning at an early stage in limb outgrowth. The temporal and spatial patterns of expression for IGF-I and its receptor are consistent with the involvement of IGF-I in the initiation of limb outgrowth (37).

POTENTIAL USE OF IGF-I AS A THERAPEUTIC AGENT IN THE SETTING OF RENAL FAILURE

Acute renal failure. Ischemic renal injury in rat results in damage to the most distal (S3) segment of the proximal tubule and, in some instances, the medullary thick ascending limbs of the loop of Henle (105). Recovery is dependent on the ability of the tubular cells to regenerate and reline the damaged areas along the nephron. Because of their potential to act as growth-promoting agents for kidney tissue, pharmacological roles for polypeptide growth factors have been proposed in the setting of acute renal failure (102). We have shown that IGF-I accelerates the recovery of normal renal function (Fig. 4) and the regeneration of damaged proximal tubular epithelium (Fig. 5) following acute ischemic renal injury in rats (70).

One rationale for use of IGF-I in the treatment of acute renal failure is that enhanced renal synthesis of IGF-I is associated with the natural regenerative process, consistent with a role for the peptide in recovery (3, 68). A second rationale is that IGF-I, known to increase the glomerular filtration rate in normal rats (see below), also exerts this effect postischemic injury (Fig. 6). Enhance- ment of glomerular filtration could alter the course of acute renal failure, possibly by limiting the extent of injury due to obstruction of tubules by cellular debris (76). Additional rationale is provided by the fact that IGF-I is a renotropic agent for the proximal tubule. It can induce hypertrophy of proximal tubule cells (42) and is postulated to be causative of the renal growth under several circumstances (see above). Furthermore, IGF-I reduces protein breakdown and exerts a generalized anabolic action that results in attenuation of weight loss in the set-

= z! I4 5 z2 I= 6 s uo !

TIME POST ISCHEMIA (days) Fig. 4. Levels of creatinine in vehicle or IGF-I-treated rats measured over time. Ischemic acute tubular necrosis was induced at time 0. Data are means f SE. * Significant differences between vehicle and IGF-I- treated groups. From Miller et al. (70).

Veh

IGF-I

Fig. 5. Photomicrographs of histological sections stained with hematox- ylin and eosin originating from kidneys of rats administered vehicle (Veh) or IGF-I for 7 days postischemic injury. Reprinted from Miller et al. (70).

ting of the catabolism that accompanies acute ischemic injury (70).

Whatever the mechanism of its action may be, a potential for the clinical use of IGF-I, a growth factor that can be safely administered to humans, as a therapeutic modality in acute tubular necrosis is clearly established (70).

Chronic renal failure. The potential for the use of IGF-I as a therapeutic agent in the setting of chronic renal failure is based on clinical and experimental observations relating to actions of GH on the kidney. O’Shea and Layish (81) have provided an excellent historical perspective of many of the studies, and a complete summary of the experimental findings within a historical context will not be repeated in this review. In short, conditions of GH deficiency in humans and in experimental animals are associated with a reduction of kidney size, glomerular filtration rate, and renal plasma flow, and states of GH excess are associated with an increase in kidney size and enhancement of glomerular filtration rate and renal plasma flow. Therefore, hypersomatotropism results in

EDITORIAL REVIEW F9

0 WEH 0 + IGF-I

p40.047

T p~O.025

NS i-4 p~O.045

I 1 1 I J

30 60 90 120 150 TIME (min)

Fig. 6. Clearances of creatinine (Ccreatinine) in rats treated with vehicle (n = 6) or IGF-I (n = 4) postischemic injury. Ischemia was induced by clamping of renal arteries for 70 min. Administration of IGF-I was begun 30 min postischemia (70). Data are means k SE. P values (Stu- dent’s t test) are shown for comparisons between vehicle and IGF-I- treated rats. NS, not significant.

both renal hypertrophy and hyperfunction. In hypersomatotropic humans the glomerular filtration rate is increased disproportionate to the increase in kidney weight. Furthermore, the reduction in glomerular filtration rate and renal plasma flow that occurs following hypophysectomy of acromegalic humans occurs more rapidly than the decrease in kidney size and is excessive relative to the decrease in kidney size. These findings indicate that, while changes in renal function may be explainable, in part, by the alterations in kidney size, there are probably other factors involved.

The actions of GH to increase kidney size and enhance glomerular filtration rate and renal plasma flow are not mediated by GH directly, but rather through IGF-I (53, 61). One mechanism by which IGF-I exerts these actions is via rapid alterations of glomerular hemodynamics. In rats, infusion of IGF-I decreases renal glomerular afferent and efferent arteriolar resistances and increases the glomerular ultrafiltration coefficient (53). Renal vasodilation induced by IGF-I can be abrogated by N-nitro-L- arginine methyl ester, an inhibitor of nitric oxide biosynthesis (49) and is reduced by the cyclooxygenase inhibitor, indomethacin (49,54), consistent with roles for the vasodilators nitric oxide and prostacyclin as media- tors of the IGF-I effect.

Given their abilities to increase glomerular filtration rate, the potential use of either GH or IGF-I as therapeutic agents in the setting of chronic renal failure has been suggested (81). However, early investigations into their utility were disappointing. For example, Haffner et al. (41) found that GH had no effect on glomerular filtration rates in seven patients with chronic renal insufficiency even though the identical dosage increased the glomerular filtration rates of individuals with normal renal function. The administration of GH to children with chronic renal insufficiency and growth failure has been found to have no significant effect on renal function despite its benefi- cial action to enhance somatic growth (28, 103). Admin- istration of IGF-I to humans (52) or to rats (69) with normal renal function increases glomerular filtration rate.

However, the administration of IGF-I to rats that had undergone one and two-thirds nephrectomy (69) or one and one-half nephrectomy (65) did not increase glomerular filtration rates compared with administration of vehicle, despite effects to enhance growth and nitrogen bal- ance.

It was suggested, on the basis of the evidence detailed above, that the uremic state is one of relative renal resis- tance to the actions of GH and IGF-I. The observations that levels of circulating immunoreactive GH are elevated in uremia, while those of immunoreactive IGF-I are normal, and the observation that IGF-I bioactivity is reduced in uremia (104) lend some credence to this hypothesis.

To address the question directly as to whether humans with reduced kidney function are responsive to the renal effects of IGF-I, we administered IGF-I to four individuals whose baseline inulin clearances were 22-55 mlmin-l.1.73 mS2 and evaluated its effects on inulin and p-aminohippurate clearances and on kidney size. We showed that IGF-I can increase glomerular filtration rate, renal plasma flow, and kidney volume in patients with moderate degrees of renal insufficiency (Figs. 7-9) (83).

Our findings illustrate differences between the rat model and actual human disease. The reasons for the difference in response between rats and humans are unknown. The magnitude of reduction in inulin clearance in rats that we studied (-17-34% of normal) (69) over- lapped the reductions in patients (l&47% of normal) (83). Therefore, differences in the extent of reduction of functional renal mass cannot explain the difference. It is possible that the model of chronic renal failure that we used in rats is not applicable to human renal disease, at least not to all human disease. In “remnant-kidney” model chronic renal failure, adaptations occur rapidly after renal mass reduction such that glomerular filtration rate increases by -50% by day 3 in the absence of IGF-I (69). We postulated that an increase in IGF-I produced by the remnant kidney is responsible for this adaptation and that exogenously administered IGF-I has no effect in the face of such an increase. We [Rogers et al. (go)] and others (55) have shown subsequently that the IGF-I content of remnant kidneys is elevated, rendering plausible our postulate.

The progressive nature of the increase in glomerular filtration rate in normal rats receiving IGF-I over a lo-

DAYS Fig. 7. Inulin clearances and levels of serum IGF-I in a patient with chronic renal failure. Solid bar, times during which IGF-I was administered. Reprinted from O’Shea et al. (83).

FlO EDITORIAL REVIEW

IGF-I

0” 5 10 ” 25 DAYS

Fig. 8. p-Aminohippurate (PAH) clearances and filtration fractions in patient with chronic renal failure whose insulin clearances are shown in Fig. 7. Reprinted from O’Shea et al. (83).

day period of time (69) suggests that the peptide may act by a second mechanism in addition to its effects on renal hemodynamics. It would be expected that the actions of IGF-I on glomerular hemodynamics would be exerted rapidly and would not be progressive. On the other hand, if IGF-I acted in addition, via its hypertrophic effect, then the progressive nature of the enhancement could be explained. The observation that the increase in creati-

nine clearance that occurred within the fiit 12 days of IGF-I administration to a Laron dwarf was progressive over the next 59 days (107) is consistent with IGF-I acting, in part, via induction of glomerular and proximal tubular hypertrophy. Such a dual mechanism of IGF-I action could explain the clinical observations that suggest a dual effect of GH (see above).

Chronic renal failure is characterized by a series of adaptations in functioning nephrons, the result of which is the preservation of relatively normal fluid and electrolyte homeostasis until late in the disease (16). One of the well-characterized functional changes following reduction of renal mass is the adaptive increase in whole kidney and single-nephron glomerular filtration rate. Micropuncture studies in rats (56) with reduced renal mass show that the elevated single-nephron glomerular filtration rate is accompanied by increased glomerular hydraulic pressure. In addition, an increase in size of remaining renal tissue occurs after renal mass reduction (62).

One potential risk that could accompany the therapeutic use of IGF-I in chronic renal failure is that of glomerulosclerosis resulting from the hyperfiltration induced by this agent. Evidence that growth-promoting agents

Fig. 9. Renal ultrasound examinations from a patient with chronic renal failure. Ultrasound examinations were performed prior to treatment with IGF-I (top) and following treatment with IGF-I for 4 days (bottom).

EDITORIAL REVIEW Fll

may be glomerulosclerotic comes from studies of rodent models of hypersomatotropism and models in which reduction of functional renal mass is effected in normal and GH-deficient rats. Hypersomatotropic rats (72) and mice transgenic for GH (23, 86) develop glomerulosclerosis. Yang et al. (109) expressed bovine GH molecules in trans- genie mice that had amino acid substitutions in the a-he- lix III region of GH. Mice transgenic for one of the ab- normal GH developed glomerulosclerosis in the absence of increased body size. These findings indicate that development of glomerulosclerosis and body growth promo- tion are mediated by different regions of the GH molecule (109).

Normal rats develop glomerular and tubular tubuloint- erstitial scarring, progressive proteinuria, hypertension, and renal failure at 120 days following five-sixths nephrectomy. In contrast, GH-deficient dwarf rats manifest only mild renal functional impairment, moderate histological scarring, and minimal proteinuria consistent with a role for GH in the alterations of renal function that accompany reduction of kidney mass (25).

It is of interest that mice transgenic for IGF-I, with levels of circulating IGF-I no different than those in mice transgenic for GH, do not develop glomerulosclerosis (23, 86). This finding is consistent with the glomerulosclerotic action of GH in rodents being mediated via a mechanism other than its action to increase the synthesis and release of IGF-I. It is noteworthy that the increase in single- nephron glomerular filtration rate induced by IGF-I in rodents is not accompanied by an increase in glomerular capillary pressure (53) as is observed in the setting of reduced renal mass (56). This difference may explain why IGF-I is not glomerulosclerotic.

Additional support for the safety of IGF-I administration in humans may be derived from the observation that, in contrast to the case in rodents, glomerulosclerosis does not occur in acromegaly (77) and chronic renal failure is not a complication of hypersomatotropism in humans. In fact, as discussed above, patients with longstanding acromegaly manifest marked renal hypertrophy and have supranormal glomerular filtration rates, suggesting that the hyperfiltration that accompanies longstanding elevations of circulating GH and IGF-I in humans does not reduce renal function (57).

There is no effective drug therapy to enhance renal function in the setting of renal insufficiency. Although much work remains to be done, and clearly caution is advised, our observations in a small number of subjects with chronic renal failure establish the potential for the use of IGF-I as a therapeutic agent in this setting.

SUMMARY AND CONCLUSIONS

Since our last editorial review (42) was published in this Journal, a rather extensive literature has accumu- lated relating to the GH-IGF axis in kidney. Agents and conditions other than GH and hypersomatotropism have been shown to regulate IGF-I gene expression in kidney. Interactions between GH, IGF-I, and other growth factors have been described in renal tissue. Both IGF-I and IGF-II have been shown to play important roles in

growth and development of the metanephric kidney. The mesonephros has been shown to have the capacity to synthesize IGF-I. A role for IGF-I in the regeneration of proximal tubule postischemic injury has been demonstrated, and a therapeutic role for IGF-I in acute tubular necrosis has been suggested. In addition, it has been shown that humans with reduced functional renal mass are not resistant to the actions of IGF-I to enhance glomerular filtration rate, establishing the potential for use of IGF-I as a pharmacological agent in the setting of chronic renal failure.

It should be noted that an extensive literature has ac- cumulated relating to the expression of a number of growth factors in kidney in addition to IGF-I and to the functions of some of these agents as regulators of renal growth, renal filtration, repair following renal injury, and nephrogenesis. Growth factors/growth factor families of importance in renal tissue include the IGF, EGF/ transforming growth factor-a, transforming growth factors-0, platelet-derived growth factor, fibroblast growth factors, nerve growth factors, and hepatocyte growth factor (43). Clearly the actions of GH-IGF-I in kidney cannot be considered in isolation. It is certain that other growth factors play major salutary or maladaptive roles in a variety of physiological or pathophysiological states and may be useful as pharmacological agents.

As was the case in 1989, our knowledge of the GH-IGF axis in kidney is incomplete. The precise role for IGF-I produced in kidney relative to circulating IGF-I as a reg- ulator of renal size, function, metabolism, and transport has yet to be defined. The function of IGFBP produced in kidney is only beginning to be explored. The relationship between GH, IGF, and the development of glomerulosclerosis in rodents and humans or of diabetic nephropathy is yet to be well delineated. A causative role for GH or IGF in abnormalities of nephrogenesis has been postulated, but to date there is no proof for such a relationship. Whether IGF, perhaps used in combination with other growth factors, will assume a place in the therapy of acute or chronic renal failure remains to be determined. The pursuit of answers to the experimental questions posed above will occupy the time of many laboratories for years to come. However, time spent thus far has been well invested. It is clear that research in this area already has spanned the distance between the laboratory and the bed- side. The GH-IGF axis in kidney will continue to be revisited.

We acknowledge the administrative assistance of Lynn Wesselmann, the technical assistance of Virginia Hansen, Daniel Martin, Sharon Rogers, and Jenny Levis Sadow. We also thank Dr. Michael O’Shea (Washington U niversity) for direction and for providing studies from which Figs. 7-9 were generated.

S. B. Miller was supported by an American Heart Association Cli- nician Scientist Award and by National Institute of Diabetes and Di- gestive and Kidney Diseases (NIDDK) Grant DK-45181. M. R. Ham- merman was supported by NIDDK Grants DK-27600, DK-45181, and DK-20579, by American Heart Association Grant-in-Aid 91006660, by Juvenile Diabetes Foundation Grant 191541, and by Genentech (S. San Francisco, CA).

Address for reprint requests: M. R. Hammerman, Renal Division Box 8126, Dept. of Internal Medicine, Washington Univ. School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110.

F12 EDITORIAL REVIEW

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F14 EDITORIAL REVIEW

81. O’Shea, M. H., and D. T. Layish. Growth hormone and the kidney: a case presentation and review of the literature. J. Am. Sot. Nephrol. 3: 157-161, 1992.

82. O’Shea, M. H., S. B. Miller, and M. R. Hammerman. In- sulin-like growth factor I and the kidney. Semin. Nephrol. 13: 96-108, 1993.

83. O’Shea, M. H., S. B. Miller, and M. R. Hammerman. Ef- fects of IGF-I on renal function in patients with chronic renal failure. Am. J. Physiol. 264 (Renal Fluid Electrolyte Physiol. 33): F917-F922, 1993.

84. Pedersen, M. M., S. E. Christensen, J. S. Christiansen, E. B. Pedersen, C. E. Mogensen, and H. Orskov. Acute effects of a somatostatin analogue on kidney function in type I diabetic patients. Diabetic Med. 7: 304-309, 1990.

85. Pillion, D. J., J. F. Haskell, and E. Meezan. Distinct receptors for insulin-like growth factor I in rat renal glomeruli and tubules. Am. J. Physiol. 255 (Endocrinol. Metab. 18): E504-E512, 1988.

86. Quaife, C. J., L. S. Mathews, C. A. Pinkert, R. E. Hammer, R. L. Brinster, and R. D. Palmiter. Histopathol- ogy associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124: 40-48, 1989.

87. Quigley, R., and M. Baum. Effects of growth hormone and insulin-like growth factor I on rabbit proximal convoluted tubule transport. J. Clin. Invest. 88: 368-374, 1991.

88. Rogers, S. A., I. E. Karl, and M. R. Hammerman. Growth hormone directly stimulates gluconeogenesis in canine renal proximal tubule. Am. J. Physiol. 257 (Endocrinol. Metab. 20): E751-E756, 1989.

89. Rogers, S. A., S. B. Miller, and M. R. Hammerman. Growth hormone stimulates IGF I gene expression in isolated rat renal collecting duct. Am. J. Physiol. 259 (Renal Fluid Electrolyte Physiol. 28): F474-F479, 1990.

90. Rogers, S. A., S. B. Miller, and M. R. Hammerman. En- hanced renal IGF-I expression following partial kidney infarc- tion. Am. J. Physiol. 264 (Renal Fluid Electrolyte Physiol. 33): F963-F967, 1993.

91. Rogers, S. A., S. B. Miller, and M. R. Hammerman. IGF I gene expression in isolated rat renal collecting duct is stimulated by epidermal growth factor. J. Clin. Invest. 87: 347-351, 1991.

92. Rogers, S. A., G. Ryan, and M. R. Hammerman. Insulin- like growth factors I and II are produced in the metanephros and are required for growth and development in vitro. J. Cell Biol. 113: 1447-1453, 1991.

93. Rotwein, P. Structure, evolution, expression and regulation of insulin-like growth factors I and II. Growth Factors 5: 3-18,199l.

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95. Sara, V. R., and K. Hall. Insulin-like growth factors and their binding proteins. Physiol. Rev. 70: 591-614, 1990.

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98. Shimasaki, S., M. Shimonaka, H. P. Zhang, and N. Ling. Identification of five different insulin-like growth factor binding proteins (IGFBPs) from adult rat serum and molecular cloning of a novel IGFBP-5 in rat and human. J. Biol. Chem. 266: 10646- 10653, 1991.

99. Stiles, A. D., I. R. S. Sosenko, A. J. D’Ercole, and B. T. Smith. Reaction of kidney tissue somatomedin-C/Insulin-like growth factor I to postnephrectomy renal growth in the rat. Endocrinology 117: 2397-2401, 1985.

100. Suikkari, A. M., I. Leivo, M. Kamarainen, H. Holthofer, M. Seppala, M. Julkunen, and R. Koistinen. Expression of insulin-like growth factor binding protein-l mRNA in human fetal kidney. Kidney Int. 42: 749-754, 1992.

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104. Tonshoff, B., F. Schaefer, and 0. Mehls. Disturbance of growth hormone insulin-like growth factor axis in uraemia. Pe- diatr. Nephrol. 4: 654-662, 1990.

105. Venkatachalam, M. A., D. B. Bernard, J. F. Donohoe, and N. G. Levinsky. Ischemic damage and repair in the rat proximal tubule: differences among the S1, Sp, and S3 segments. Kid- ney Int. 14: 31-49, 1978.

106. Vora, D. R. Owens, S. Luzio, A. Atiea, R. Ryder, and T. M. Hayes. Renal response to intravenous somatostatin in insulin-dependent diabetic patients and normal subjects. J. Clin. En- docrinol. Metab. 64: 975-979, 1987.

107. Walker, J. L., J. J. Van Wyk, and L. E. Underwood. Stimulation of statural growth by recombinant insulin-like growth factor I in a child with growth hormone insensitivity syndrome (Laron type). J. Pediatr. 121: 641-646, 1992.

108. Werner, H., 2. Shen-Orr, B. Stannard, B. Burguera, C. T. Roberts, Jr., and D. LeRoith. Experimental diabetes increases insulinlike growth factor I and II receptor concentration and gene expression in kidney. Diabetes 39: 1490-1497, 1990.

109. Yang, C.-W., L. J. Striker, C. Pesce, W. Y. Chen, E. P. Peten, S. Elliot, T. Doi, J. J. Kopchick, and G. E. Striker. Glomerulosclerosis and body growth are mediated by different portions of bovine growth hormone. Lab. Invest. 68: 62-70,1993.

110. Zumkeller, W., and P. N. Schonfield. The role of insulin-like growth factors and IGF-binding proteins in the physiological and pathological processes of the kidney. Virchows Arch. I3 Cell Pathol. 62: 207-220, 1992.

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