Hammerman AJP 1989 GHIGF1 Axis

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

MARC R. HAMMERMAN Renal and Endocrine Divisions, Departments of Internal Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

HAMMERMAN, MARC R. The growth hormone-insulin-like growth factor axis in kidney. Am. J. Physiol. 257 (Renal Fluid Electrolyte Physiol. 26): F503-F514, 1989.-Growth hormone (GH) exerts a variety of metabolic and anabolic effects on skeletal and soft tissues including kidney. Some of these actions are mediated directly, whereas others result from GH-dependent synthesis and release of polypeptide growth factors designated insulin-like growth factors (IGFs). Receptors for GH are present in proximal tubule and GH directly stimulates gluconeogenesis at this site. IGF receptors are found in glomerulus and proximal tubule. Mechanisms for signal transduction by GH and IGFs have been characterized using proximal tubular basolateral membranes. IGFs regulate metabolic and transport processes in cultured glomerular mesangial cells and in isolated proximal tubular cells. IGF I is synthesized in cultured mesangial cells and is produced in a GH-dependent manner in cortical and medullary collecting duct. Evidence has accumulated that IGF I of renal origin functions as a paracrine growth factor in the settings of GH-induced hypertrophy and compensatory hypertrophy of the kidney, and in the setting of proximal tubular regeneration following ischemic injury. IGFs are embryonal mitogens and IGF II may act as a transforming agent for Wilms’ tumor. Further characterization of the GH-IGF axis in kidney will provide additional insights into the roles of these peptides as regulators of renal function, growth, and development.

collecting duct; glomerulus; insulin; metanephrogenesis; phospholipase C; proximal tubule; renal hypertrophy; renal metabolism

IT WAS THOUGHT INITIALLY that all actions of growth hormone (GH) were exerted directly on target tissues. However, in 1956 Salmon and Daughaday (79) discovered that the effect of GH to stimulate incorporation of 35S04 into rat cartilage was not a direct one, but rather was mediated through a circulating “sulfation factor.” The term somatomedin was introduced in 1972 to refer to sulfation factor and other circulating factors that had been shown to mediate a variety of growth-promoting actions of GH (somatotropin). The proposal that these actions are not exerted directly is known as the somatomedin hypothesis. Somatomedins were isolated initially from human and animal serum on the basis of activities defined in bioassay systems. It was found subsequently that biological activities attributed to these factors could be explained on the basis of two peptides, each of which has -50% homology to proinsulin. Accordingly, these peptides were designated insulin-like growth factors I

and II (IGFs I and II) (18). Because GH stimulates the synthesis and release of IGFs and circulating IGFs exert negative feedback on GH secretion, these peptides are considered to participate in a hormonal axis. Growth processes and metabolic functions of most tissues are regulated by the GH-IGF axis (17).

Administration of GH to normal or hypopituitary humans or experimental animals affects several parameters of renal function. Thus this peptide increases glomerular filtration rate, renal plasma flow, proximal tubular reabsorption of phosphate (15, 16), and proximal tubular gluconeogenesis (54). In addition, GH induces hypertrophy of glomerulus and proximal tubule (34). Until re- cently, little was known about the mechanisms by which these actions of GH are effected, or about the roles of IGFs in their mediation. However, in the past several years studies originating from a number of laboratories have shed new light on the GH-IGF axis in kidney. These

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investigations have provided important insights into processes of signal transduction by GH and IGFs in renal tissue and into the nature of metabolic processes regulated by GH and IGFs along the nephron. In addition, they have established that kidney is a site for GH- stimulated and GH-independent IGF production. The data from these investigations indicate that locally produced IGFs are inducers of renal hypertrophy, and may act as effecters of renal organogenesis, as factors causative of proximal tubular regeneration following ischemic injury, and as transforming agents. The purpose of this review is threefold: first, to provide a background for discussion of GH and IGF actions in renal tissue; second, to relate observations made in vitro to the roles of GH and IGFs to regulate renal function, renal growth, and renal development; and finally to speculate regarding future areas of investigation.

Growth Hormone and IGFs-Biochemistry, Physiology, Cellular and Molecular Biology

Growth hormone. Human growth hormone (hGH) (Fig. 1) is a single-chain polypeptide of 191 amino acids, which is synthesized in the anterior lobe of the pituitary gland (11). It is related structurally to human chorionic soma- tomammotropin, a peptide secreted by the placenta, and to prolactin, which is also an anterior pituitary hormone (84). GH-related peptides of mammalian species have diverged from a common ancestor peptide (84). Most mammalian GH molecules are similar in structure. How- ever, primate GH has diverged more from the ancestor

peptide than nonprimate GH. Changes in the primate GH receptor have accompanied the changes in the GH molecule. As a result, humans do not respond to GHs of nonprimate origin (84).

Most pituitary GH has a molecular mass of 22 kDa, however, -10% is missing 13 amino acid residues present in the 22-kDa form and has a molecular mass of 20 kDa. The human GH gene is present on the long arm of chromosome 17. It contains five exons and four introns. Alternative splicing of the primary mRNA transcript results in mRNAs that code for 22-kDa GH and the 20- kDa variant (11, 35).

Secretion of GH is regulated by a hypothalamic GH- releasing factor and by an inhibitory factor, somatostatin. Release of these peptides is in turn modu- lated by a number of neuropeptides and endogenous opiates (17). Circulating GH exerts negative-feedback control on itself by both inhibiting GH-releasing factor secretion and stimulating somatostatin release (17). In addition, circulating IGFs exert feedback on GH secretion by inhibiting the stimulatory action of the releasing factor (17). GH is secreted by the pituitary in surges. A major secretory peak occurs l-2 h after the onset of deep sleep. Other physiological stimuli for GH release include physical exercise, hypoglycemia, and ingestion of a high- protein meal (17). The latter two stimuli reflect the role of GH as a counterregulatory or glucose-elevating peptide. The need for secretion of a glucose-elevating agent in the setting of hypoglycemia is obvious. The physiological role of GH secretion following ingestion of a pure

FIG. 1.

copyright

55 50

Covalent structure of human growth hormone [Reprinted with permission from Annu. Rev. Med., vol. 34, 1983 by Annual Reviews Inc. (ll).]

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INSULIN PROINSULIN ICF 111 IGF (2)

FIG. 2. Schematic diagram of insulin, proinsulin, insulin-like growth factor (IGF) I, and IGF II. [From Honnegger

F505

et al. (50).]

protein meal may be to counteract the glucose-lowering action of insulin, the release of which is also stimulated by protein intake (3).

Circulating GH acts both directly on sensitive cells and via its stimulation of IGF production. It is generally accepted that its actions to regulate glucose metabolism are exerted directly, whereas stimulation of somatic growth is indirect (32). Actions of GH are exerted following binding of hormone to specific plasma membrane receptors. Cloned cDNA sequences of rabbit and human GH receptors predict proteins of 620 amino acids with a single, centrally located transmembrane domain and five potential N-glycosylation sites in the extracellular region (58). Studies employing affinity-crosslinking techniques have demonstrated a heterogeneity of 1251-labeled GH- receptor complexes, with one group migrating at relative molecular weight (A&) 55,000-80,000 and a second group at A& llO,OOO-140,000 (51, 52). The relationships and structural differences between these complexes are not clear. The heterogeneity could reflect differences in co- valently linked carbohydrate chains, crosslinking of 1251- GH to subunits, or breakdown of the holo-receptor (52). Little is known about the mechanism by which GH signal transduction takes place. Much of what is known origi- nates from studies conducted using isolated renal proximal tubular basolateral membranes, which will be discussed below.

Insulin-like growth factors. IGF I and IGF II are single- chain insulin-like polypeptides 70 and 67 amino acids in length, respectively (Fig. 2). In humans, the concentra- tion of IGFs in circulation is -lo-' M, which is about 100 times higher than circulating insulin. Because the insulin-like potency of IGFs approximates 5% of that of insulin itself, the pool of circulating IGFs has the potential to contribute more insulin-like activity than insulin (7). This activity is not expressed in vivo, probably as a result of tight noncovalent binding of IGFs to specific carrier proteins. The affinity of IGFs for their carrier peptides is high enough that virtually no free IGF I or IGF II is measurable in serum (17).

The role of the IGF carrier proteins in mediation or regulation of IGF actions at cellular sites is unclear. These peptides have been shown to both inhibit (27) and stimulate (28) actions of IGFs measured in vitro. At

neutral pH, most of the bound IGFs are present in a complex of 150,000 2M,. This component of IGF-carrier protein is GH-dependent and virtually disappears from circulation in the setting of hypopituitarism. Normal serum also contains a smaller amount of a 35,000-M, binding protein that is immunologically distinct from the larger peptide and that is the major binding protein in pituitary deficiency ( 17).

GH provides the major stimulus for production of IGF I in liver, kidney, and other tissues. In addition, nutri- tional status plays an important role in IGF production. Thus levels of circulating IGF I are markedly reduced in a variety of conditions associated with negative calorie and nitrogen balance (17). IGF II, like IGF I is produced in a number of tissues, but is much less GH dependent (17). A growing body of evidence suggests that IGFs produced in tissues act as local growth factors. Thus their targets are the cells in which they are made (autocrine growth factor) or adjacent cells within the same tissues (paracrine growth factor). Therefore, tissue levels of IGFs may be of greater physiological significance than levels of peptides in circulation (20, 25).

Single genes code for each IGF. In humans the IGF I gene is on chromosome 12, while the insulin and IGF II genes are on the short arm of chromosome 11 (9, 82). Sequence analysis of the IGF I gene reveals a discontin- uous structure, consisting of five exons and four introns spanning a region of 45 or more kilobases (77). The IGF II gene consists of at least seven exons spanning >30 kilobases (19). Several different IGF I and IGF II mRNAs result from alternative processing of the primary gene transcript (19, 77).

INSULIN IGFI IGF II cxa aoc

FIG. 3. Schematic representation of plasma membrane receptors for insulin, insulin-like growth factor (IGF) I, and IGF II. [From Ham- merman (38) .]


IGFs bind to specific receptors present on the plasma membranes of sensitive cells (Fig. 3). The IGF I receptor is a tetrameric glycoprotein similar in structure to the insulin receptor. It consists of two cu-subunits each with a M, of -135,000 and two ,&subunits each with a M, of -92,000 (70). As is the case for insulin, binding of IGF I to the a-subunit of its receptor results in autophosphor- ylation of the P-subunit. It is proposed that this phosphorylation event is involved in transmission of the insulin and IGF I signals across the plasma membrane. In contrast, the receptor for IGF II is a monomer with a M, of -260,000 (70).

Amino acid sequences deduced from cDNA clones encoding the IGF II and cation-independent mannose-6- phosphate receptors show that they are identical structures (62). This cation-independent mannose-6-phosphate receptor is thought to participate in translocation of newly synthesized lysosomal proteins containing a mannose-6-phosphate recognition marker to lysosomes. In addition, receptors present in plasma membranes are proposed to effect endocytosis of extracellular mannose- 6-phosphate-containing peptides (55). IGF II and mannose-6-phosphate bind to separate sites on the protein (59). The physiological significance of the identity between IGF II and cation-independent mannose-6-phosphate receptors is unclear. However, insight into the meaning of the identity has been provided by studies conducted using isolated proximal tubular basolateral membranes, which will be discussed below.

The mechanism by which IGF II signal transmission occurs is not known with certainty, although a mechanism for signaling has been identified in proximal tubule (see below). The exact biological function of this peptide is undefined. Several actions of IGF II in vitro appear to be mediated via an interaction of IGF II with receptors for insulin or IGF I. However, a number of laboratories have demonstrated effects of IGF II in vitro that are clearly mediated through the IGF II receptor (76).

IGFs regulate a variety of metabolic and transport processes in isolated cells and act as mitogens for many cell types (7, 20, 33) including transformed cells (85). Under some circumstances in vitro, IGF I acts in concert with other polypeptide growth factors, termed compe- tence factors, in exerting mitogenic actions. The com- petence factors render quiescent cells capable of respond- ing to IGF I (20). In addition to their metabolic and mitogenic effects, IGFs exert differentiative actions in vitro, especially on cells of mesodermal origin (33).

It is likely that IGFs play a role in fetal growth and development, since multiple fetal tissues synthesize these peptides and/or have IGF receptors (20). The fetal pituitary is not required for maintenance of normal levels of circulating IGF I. Therefore, production of IGF I in the fetus is GH-independent, at least in part. In rats but not in humans levels of circulating IGF II and IGF II mRNA present in several tissues, including kidney, de- cline precipitously following birth. This observation suggests that IGF II functions as a fetal growth factor in rat (10) .

GH, IGFs, and Kidney Metabolism of GH and IGFs in kidney. The kidney

plays an important role in the metabolism of circulating GH. In rat, this organ accounts for -70% of total GH turnover (69). The peptide is removed from circulation by glomerular filtration followed by highly efficient reabsorption and catabolism in proximal tubule (53). Prod- ucts of GH metabolism are subsequently released back into the circulation. There is evidence that reabsorption of GH from glomerular ultrafiltrate is effected by endocytosis that occurs following binding of GH to the luminal membrane (53). However, the structure of the GH receptor in the luminal membrane and the specificity of the binding process have not been completely characterized.

Kidney is a site of IGF I degradative activity (22). As discussed above, the major circulating IGF-binding protein complexes have Mrs of approximately 150,000 and 35,000. It is likely that a fraction of the smaller complex enters glomerular ultrafiltrate, and the IGF entering in association with it is metabolized in proximal tubule.

Effects of GH and IGFs on renal function. As described above, GH is known to increase glomerular filtration rate and renal plasma flow, enhance proximal tubular reabsorption of phosphate, and stimulate renal gluconeogenesis (15, 16, 54). Most of the studies demonstrating effects of GH on these processes have been carried out in humans or animals in whom/which levels of circulating GH have been altered by hypophysectomy, the presence of GH-secreting tumors, or administration of GH. Therefore, they do not provide insight into whether the actions of GH described are mediated directly or indi- rectly via IGFs. Evidence that glomerular filtration rate and renal plasma flow are not directly affected by GH is supplied by observations that these parameters are un- changed during short-term infusion of GH in normal humans (65). Additional evidence consistent with an indirect action of GH is provided by studies demonstrating a delayed effect of GH infusion in normal humans to increase glomerular filtration rate and renal plasma flow. It was shown that changes in these parameters occurred only after levels of circulating GH fell to normal. How- ever, levels of circulating IGF I were elevated at the time of the increases (49). A causative role for GH-stimulation of IGF I in these changes of renal function is supported by the observation that infusion of IGF I alone into fasted rats increases glomerular filtration rate and renal plasma flow in fasted rats (48), and increases creatinine clearance in humans (36).

The action of GH to enhance reabsorption of phosphate in proximal tubule results from an increase in the Vmax of the Na+-dependent phosphate transporter in the brush-border membrane (41). However, it is not known whether this represents a direct action of GH or whether the effect on phosphate reabsorption is mediated through IGFs. The findings that IGF I stimulates Na+-dependent phosphate transport in cultured kidney cells (lOa) is consistent with the latter possibility. As will be discussed below, the action of GH to stimulate proximal tubule is a direct one.

gluconeogenesis in

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GH and IGFs-Receptors and Signal Transduction in Renal Tissue

GH receptors have been identified in isolated proximal tubular basolateral membranes (74). Incubation of basolateral membranes with GH results in production of inositol-trisphosphate and diacylglycerol from endogenous phosphatidylinositol-4,5-bisphosphate, demonstrating activation of phospholipase C (74). One or more products of this activation could mediate GH signal transduction across the plasma membrane of the renal proximal tubular cell and elsewhere.

Receptors for IGF I have been identified in cultured glomerular mesangial cells (1,5,6, 13), and receptors for both IGF I and IGF II in glomeruli (47, 67, 83), and in proximal tubule (39,40,42,67). Studies carried out using isolated basolateral and brush-border membranes have shown that the distribution of IGF I receptors in proximal tubule is asymmetrical, localization being predominantly on the basolateral side (42). In contrast, IGF II receptors are symmetrically distributed between basolat- era1 and brush-border membranes (42). IGF I-stimulated protein kinase activity is present in isolated basolateral membranes (Fig. 4). As in nonrenal membranes, the fi- subunit of the IGF I receptor is its own substrate (40). IGF II activates a phospholipase C in isolated basolateral

Phosphorylation Immunoprecipitation

I-92,000-

0 Ins IGFI 0 Ins IGFI

(B-10)

FIG. 4. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Shown are autoradiograms originating from sol- ubilized basolateral membranes incubated with lo-’ M insulin or 10d6 M insulin-like growth factor (IGF) I or with neither peptide (0) prior to exposure to [-y-‘“P]ATP. Also shown are autoradiograms originating from immunoprecipitates of phosphorylated membranes incubated with antibody BlO that is specific for insulin receptor. “‘P-phosphorylated p-subunit of insulin receptor is immunoprecipitated. However, & subunit of the IGF I receptor is not. Region in vicinity of 92,000 M, is shown. [From Hammerman and Gavin (40).]

CIGF II]. M CIGF It], M

FIG. 5. Stimulation of inositol trisphosphate (Ins-Ps) production and diacylglycerol production by recombinant human insulin-like arowth factor (IGF) II in isolated renal proximal tubular basolateral membranes. Data represent means + SE of 3 experiments performed as described previously (72). Free calcium was 0.2 PM.

membranes, producing inositol-trisphosphate and di- acyglycerol from endogenous phosphatidylinositol-4,5- bisphosphate (Fig. 5). Neither insulin nor IGF I has a similar action (72). This process is likely to reflect one mechanism by which the IGF II signal is transmitted across the membrane in vivo. Activation of phospholipase C by IGF II in basolateral membranes is potentiated by mannose-6-phosphate (73). This finding provides the first insight into the physiological “meaning” of the homology between IGF II and cation-independent mannose 6-phosphate receptors. Participation of free mannose-6-phosphate in IGF II signal transduction in vivo is unlikely. However, it is possible that the actions of free mannose 6-phosphate in isolated basolateral membrane reflect those of mannose-6-phosphate-containing peptides to modulate signal transduction by IGF II in vivo (73, 76).

GH and IGFs-Actions on Renal Metabolism and Transport

GH, IGF I, and IGF II exert distinct direct actions on metabolic and transport processes in isolated proximal tubular cells. Both GH and IGF I enhance gluconeogenesis (75). Neither insulin (12), nor IGF II (75) has a similar action. Enhancement of gluconeogenesis at this site is likely to play a role in the counterregulatory action of GH. IGF II, but neither insulin nor IGF I stimulates Na’-H+ exchange across the brush-border membranes of proximal tubular cells (61). The Na+-H’ exchanger in a number of cell types is activated by polypeptide growth factors. Changes of intracellular pH resulting from such activation are thought to play a role in growth factor signaling (61). It is possible that the effect of IGF II to alkalinize proximal tubular cells through stimulation of the Na+-H’ exchanger reflects such a signalling process.

Synthesis of IGFs in renal tissue. It was shown by McConaghey and Dehnel that perfusion of kidneys isolated from normal or hypophysectomized rats with GH increased sulfation factor activity present in effluents (60). This observation provided the first evidence that IGFs are synthesized in kidney. D’Ercole et al. (25) demonstrated that administration of GH to hypophysectomized rats enhances levels of IGF I extractable from a variety of organs, including kidney, prior to any changes in circulating IGF I. It was found subsequently that GH administration to hypophysectomized rats increases lev-

FIG. 6. Immunohistochemical localization of insulin-like growth factor (ICF) I in rat kidney. Top: A, rat cortex, control (IGF I-antiserum run through an IGF I-affinity column to absorb IGF I antibody) (57); Z3, rat cortex, IGF I- antiserum (antiserum run through an affinity column to which no IGF I was affixed); C, rat medulla, control; D, rat medulla, IGF I antiserum. A 1:lOO dilution of absorbed or nonabsorbed antiserum was used for immunostaining. Bottom: A, hypophysectomized rat cortex, IGF I antiserum; B, hypophysectomized rat cortex obtained following 8 days of growth hormone (GH) administration (8), IGF I-antiserum; C, hypophysectomized rat medulla, IGF I- antiserum; D, hypophysectomized rat medulla obtained following 8 days of GH administration, IGF I-antiserum. A 1:250 dilution of IGF I-antiserum was used for immunostaining.

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-182 nt

4 2 1 0.5 0.2 0.1 0.05 WK CD GL PT Y

LIVER KIDNEY hl hJ9)

els of IGF I mRNA in multiple sites including renal tissue (8, 63). These findings establish that IGF I is synthesized in kidney and suggest a paracrine or autocrine mechanism of action.

Several groups of investigators have localized IGF I within intact kidney to collecting ducts by use of immu- nohistochemistry (4a, 8, 44, 45). The presence of immunostainable IGF I in cortical and medullary collecting ducts of rat kidney is illustrated in Fig. 6 (top). IGF I mRNA is colocalized in collecting duct as shown in Fig. 7, which depicts the results of a solution-hybridization nuclease-protection experiment. The steady-state level of IGF I mRNA in collecting duct is -25% of that found in liver (8). The level of immunostainable IGF I in collecting duct is regulated by GH. Thus administration of GH to hypophysectomized rats results in enhanced staining of IGF I at this site, but no detectable IGF I in other portions of the nephron (Fig. 6, bottom). Hypophy- sectomy of rats reduces steady-state levels of IGF I mRNA in collecting duct, and administration of GH to hypophysectomized rats increases IGF I mRNA as illustrated in Fig. 8. Five different species of IGF I mRNA are identifiable in collecting duct (Fig. 9) and each is GH

LIVER f 1

4 2 1 NJ

coFE?g ‘C Hd

-182 nt

FIG. 8. Autoradiograms depicting result of a solution-hybridization nuclease-protection experiment performed as in Fig. 7. Illustrated are protected RNA fragments originating from rat liver or from 8 rg of total cellular RNA originating from collecting ducts from control rats (C), hypophysectomized rats (H), or hypophysectomixed rats to which growth hormone was administered (GH). [From Lajara et al. (57).]

5’ probe

ii;

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F IG . 7. Autoradiogram depicting result of a solution-hybridization, nuclease-protection experiment, using a “P-labeled rat insulin-like growth factor (IGF) I exon 3 antisense probe (protected fragment = 182 nucleotides). II- lustrated are protected RNA fragments originating from rat liver, whole kidney (WK), collecting duct (CD), glomeruli (GL), proximal tubule (PT), or yeast tRNA (Y). [Reprinted from J. Cell Bill., 1988, vol. 107, p. 811-818, by copyright permission of the Rockefeller University Press (8).]

3’ probe

, -192nt

I

-d , u

I I

LIVER LIVER CD (I41 hJd hJd

FIG. 9. Autoradiograms depicting results of a solution-hybridization nuclease-protection experiment using 32P-labeled rat insulin-like growth factor (IGF) I antisense RNA probes spanning slice sites located at 5’ and 3’ ends of the gene. Protected fragments originating from rat liver or renal collecting duct (CD) are 194, 148, 72, 192, and 105 nucleotides in length [From Lajara et al. (57).]

dependent (57). This reflects alternative processing of the primary gene transcript.

The findings described above demonstrate colocaliza- tion of IGF I and IGF I mRNA in collecting duct of adult rat kidney, consistent with focal expression of the IGF I gene at this site. Receptors for IGF I are present in proximal tubular basolateral membranes of adult rat kidney, but not in plasma membranes from collecting duct (57) (Fig. 10). Such a distribution of receptors is consistent with a role for IGF I produced in collecting duct as an effector of biological actions in proximal tubule (paracrine action). It can be appreciated from Fig. 6 (top and bottom) that the basolateral membrane of the proximal tubular cell is immediately adjacent to cortical collecting duct that contains immunostainable IGF I. Presumably, peptide could diffuse easily from the latter to the former location. The site of action for IGF I


Coil Duct Prox Tub BLM Rat Doa Rat

-135,000

3 lO+M IGF I FIG. 10. Autoradiograms from a sodium dodecyl sulfate-polyacryl-

amide gel electrophoresis of rat collecting duct (co11 duct) or proximal tubular basolateral membranes (Prox Tub BLM) from rat or dog kidnev. Membranes were cross-linked with lo-“’ M ‘94abeled insulin- like growth factor (IGF) I in absence or presence of 10m6 M IGF I. Region in vicinity of a-subunit of the IGF I receptor (135,000 A4,) is shown. [From Lajara et al. (57).]

produced in medullary collecting duct may be the same or different from that of peptide produced in cortex. A clue to the function of IGF I produced in medulla is provided by consideration of the renal venous circulation and structure of the renal veins. Renal medulla is drained by ascending vasa recta. The walls of these vessels are extensively fenestrated. Indeed, their structure is fun- damentally the same as walls of renal capillaries. True capillaries, derived from branches of efferent arterioles, are few in the outer stripe of medulla and segments of proximal tubule and other tubular structures at this site are supplied mainly by venous blood from deeper parts of the medulla provided by the fenestrated vasa recta (56). It is possible that IGF I produced in renal medulla acts on structures in the outer stripe of medulla following transport via the vasa recta.

Glomerular mesangial cells in culture originating from mouse (13) and human (6) kidneys have been shown to synthesize and release IGF I, although GH does not stimulate this process (13). Since receptors for IGF I are present in mesangial cells (1, 5, 6) and mesangial cells exhibit a mitogenic response to the peptide (14), it is possible that IGF I is an autocrine growth factor in the

glomerular mesangium. IGF I produced in glomerular mesangial cells could play an etiological role in prolifer- ative glomerulopathies (6). This suggestion is supported by observations made in transgenic mice that have high levels of circulating GH and develop a progressive glomerulosclerosis (26, 28). However, mice transgenic for IGF I do not develop similar lesions (68), consistent with GH itself being causative of glomerulosclerosis.

IGF I in states of renal hypertrophy. A causative role for GH or IGF I in renal hypertrophy is suggested by the hypertrophic response of the glomerulus and proximal tubule that accompanies the elevation in levels of circulating GH and IGF I that occurs in acromegaly (34). Such a role is supported by the observation that administration of GH or IGF I to hypophysectomized rats results in kidney growth (37). A renotropic function for IGF I as a locally synthesized growth factor is suggested by studies that demonstrate increased IGF I extractable from kidney or measurable in collecting duct in two types of renal hypertrophy, that which accompanies administration of GH to hypophysectomized rats (8, 25, 81) and that which follows unilateral nephrectomy, so-called compensatory renal hypertrophy (4a, 30,57,81).

The “compensatory” hypertrophy of the contralateral kidney, which follows loss of a kidney in humans and unilateral nephrectomy of experimental animals is measurable within l-2 days (31). As in acromegaly (34) the hypertrophy involves predominantly glomerulus and proximal tubule (31). No changes in radioimmunoassay- able IGF I extractable from kidney (30, 81) or immunostainable IGF I in collecting duct (4a, 57) occur in the first 2 days postnephrectomy. This suggests that IGF I is not involved in the early hypertrophic response. How- ever, immunostainable IGF I in collecting duct (4a, 57) and IGF I extractable from whole kidney (30, 81) are increased by the 3rd-5th postoperative day. These observations are consistent with a role for IGF I during the later phases of compensatory renal hypertrophy.

Levels of IGF I mRNA have been measured in whole kidneys and collecting ducts originating from unine- phrectomized and sham-operated rats. “Dot-blot” analysis showed that levels of IGF I mRNA in hypertrophied kidneys from nephrectomized rats were increased (30). However, no changes in any of five species of IGF I mRNA in hypertrophied kidneys or collecting ducts from hypertrophied kidneys could be detected 1, 2, 5, or 14 days postnephrectomy using more sensitive solution- hybridization nuclease-protection assays (57). Thus, un- like the case for GH-induced hypertrophy (Fig. 8) (8,57), changes in immunostainable IGF I in collecting duct in the setting of compensatory hypertrophy are not accompanied by parallel changes in steady-state levels of IGF I mRNA (Fig. 11). This could be explained by enhanced translation of one or more species of IGF I mRNA in response to an as yet undefined stimulus in compensatory hypertrophy.

IGFs and renal organogenesis. Three distinct types of renal excretory organs exist in vertebrates. The most primitive of these is the pronephros, which functions only in some of the lower fishes. In higher fishes and amphibians, the mesonephros, located further caudally,

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IGF-I Collecting Duct SHAM NX

n- LIVER c 1

C 1 5 I4 I 5 14doys 4 2 pg

t

-182 nt

F511

FIG. 11. Autoradiograms depicting result of a solution-hybridization, nuclease-protection experiment, performed as in Fig. 7. Illustrated are protected RNA fragments originating from rat liver or from 8 ug of total cellular RNA originating from collecting ducts from control rats (Cl, rate that underwent unilateral nephrectomy (NX) at 1, 5, or 14 days before death, or rats that underwent “sham” surgery (SHAM). [From Lajara et al. (57).]

is the functional renal excretory organ. In birds and mammals, a third excretory organ develops caudal to the mesonephros. This is the metanephros (66).

In recapitulation of phylogeny, the pronephros, mesonephros and metanephros are formed in succession during the development of avian and mammalian embryos. The pronephros is wholly vestigial. The mesonephros, formed further caudally, functions in embryonic life, but disappears in the adult except for parts of its duct system that become associated with the male reproductive organs. The metanephros, located most caudally, is the last of the renal excretory organs to appear. It becomes functional toward the end of embryonic life and persists as the permanent kidney of the adult (66).

The pronephros, mesonephros, and metanephros are all paired organs derived from the intermediate mesoderm that is located immediately lateral to the somites. Pronephric tubules empty into the primary nephric duct. The ducts are appropriated by the developing mesonephros, and after degeneration of the pronephric tubules are designated mesonephric ducts. These ducts empty into the cloaca. At a later stage in development outgrowths develop from the mesonephric ducts near their cloaca1 ends. These so-called metanephric diverticula, or ureteric buds, collect about their distal ends intermediate mesoderm caudal to the mesonephros. This mesoderm gives rise to the excretory tubules of the metanephros, and for that reason is designated metanephrogenic mesoderm or mesenchyme. Numerous outgrowths arise from the distal end of the ureteric bud which push radially into the surrounding mass of metanephrogenic mesen- thyme. These outgrowths become hollow and give rise to the collecting ducts of the kidneys. The proximal ends of the ureteric buds give rise to the ureter and renal pelvis (66).

The terminal portions of the ureteric bud induce the formation of metanephric tubules in the surrounding metanephrogenic mesenchyme. In the absence of ureteric bud, tubules do not appear and unilateral renal agenesis

results. The inducer function of the ureteric bud for differentiation of metanephrogenic mesenchyme has been studied in metanephric organ culture. Both isolated ureteric bud and metanephrogenic mesenchyme fail to differentiate in the absence of contact with the other tissue. When the two tissue components are combined and grown together, tubule formation is triggered in the mesenchyme. Studies demonstrating induction of mesenchyme by ureteric bud or other inducer tissue present on the opposite side of a filter are consistent with a humoral factor or factors as causative of the inductive event (29). Demonstration of IGF I gene expression in collecting duct of adult kidney may be particularly rele- vant to the metanephrogenic process because ureteric bud, the inducer of metanephrogenesis in vivo, and an inducer of metanephrogenesis in vitro, is the fetal anlage of collecting duct (66).

A role for locally produced IGFs in renal organogenesis is suggested by several lines of investigation. First, receptors for both IGF I and IGF II are present in fetal renal tissue, establishing the potential for IGF-mediated signal transduction (23, 64). Second, synthesis of IGF I occurs in mammalian fetal kidney. Thus the peptide is produced by renal explants from 17-day mouse embryos (21) as well as in human fetal kidney (24) where immunostainable IGF I is present in the lining columnar epithelium of proximal and distal convoluted tubules and in collecting ducts (44). In humans, IGF I and IGF II mRNA were localized to the renal capsule, calyces, and interstitium of inner cortex and medulla using in situ hybridization (43).

Rotwein et al. (78) characterized IGF I gene expression during days 11-14 of rat embryonic development. They found that steady-state levels of IGF I mRNA in whole embryos are detectable as early as day 11 of development and rise 8.6-fold over the ensuing 48 h. This period is characterized by a rapid increase in the size of the embryo and differentiation of many organ systems including metanephric kidney (2). In contrast, levels of IGF II

F512 EDITORIAI

mRNA are relatively constant over days 1 l-14 of gestation. These observations suggest that both IGFs may play important roles in early fetal and renal development (78) .

Other Actions of IGFs in Kidney-Regeneration Following Ischemic Injury and Malignant Transformation

A role for IGF I in regeneration of the proximal tubule following ischemic injury in the rat is suggested by the studies of Andersson and Jennische (4). These investigators found no IGF I immunoreactivity in the S3 region of proximal tubule under normal conditions. However, within 3 days following induction of ischemic injury, low regenerating tubular cells expressing IGF I immunoreactivity could be demonstrated invading the damaged region. At 5 and 7 days postischemia some of the regenerating cells showed immunoreactivity, while adjacent and similar-appearing cells did not. At 14 days postinjury, the S3 cells had regained normal morphology, and IGF I immunoreactivity was no longer detectable (4). It was proposed that a transient increase in expression of IGF I occurs in the early phase of postischemic regeneration in rat proximal tubule. The cells expressing IGF I immunoreactivity were not identified with certainty. The authors note that they may be undifferentiated proximal tubular cells or cells from more distal portions of the nephron, which migrate into the ischemic region. What- ever the origin of the IGF I-containing cells, their presence in postischemic proximal tubule is consistent with a role for locally produced IGF I in the regenerative process.

A possible role for IGF II as a transforming growth factor has been described in studies of Wilms’ tumor (46, 71, 80). Reeve et al. (71) found that the level of IGF II transcripts in tumor tissue is highly elevated compared with the level in adjacent normal kidney. Furthermore, the gene for IGF II is in the immediate vicinity of the tumor susceptibility gene on chromosome 11. It was proposed that IGF II expression occurs in Wilms’ tumor as the result of a regulator gene being inactivated or eliminated from the tumor cells. Scott et al. (80) found that expression of the IGF II gene in Wilms’ tumor was markedly increased compared with adult tissues, but was comparable to the level of expression in several fetal tissues including kidney. These investigators also suggested that IGF II may contribute to the transforming process but noted alternatively that IGF II expression may reflect the state of tumor differentiation.

Summary and Conclusions

Much has been learned about GH and IGFs from studies characterizing their effects on renal function and their interactions with renal tissue. Several lines of evidence indicate that the glomerulus and proximal tubule are target tissues for both peptides. Thus 1) GH and IGFs regulate glomerular filtration rate, renal plasma flow, phosphate transport, and gluconeogenesis in intact kidney as well as metabolic activities and transport functions in cultured glomerular mesangial cells and isolated

REVIEW

proximal tubular cells; 2) receptors for GH have been identified in proximal tubule, and those for IGFs I and II have been found in glomerulus and proximal tubule; and 3) mechanisms for signal transduction by GH and IGFs have been characterized in proximal tubule.

The kidney is a site of IGF I biosynthesis. The peptide is produced in cultured glomerular mesangial cells and in collecting duct. Synthesis at the latter site is regulated by GH. Evidence has accumulated to suggest that IGF I made within kidney acts as a renal growth factor in the settings of GH-induced hypertrophy, compensatory hypertrophy, and postischemic regeneration of proximal tubule. In addition, IGF I could play a role in metanephrogenesis. IGF II may be transforming growth factor for Wilms’ tumor.

Our knowledge of the GH-IGF axis in kidney is incom- plete. A number of important questions about the functions of these peptides remain to be addressed. For example, it is likely that factors other than GH regulate IGF I gene expression in renal tissue. However, the identity of these factors and the circumstances under which they act are unknown. The nature of feedback loops for GH and IGFs in kidney is undefined. Sites of action for GH and IGF probably exist along the nephron in addition to those that have been characterized. In addition, interactions may occur between GH, IGFs, and other polypeptide growth factors in renal tissue. Future investigations will address these and other issues and will expand our understanding of the role of the GH-IGF I axis in the regulation of renal function, growth, and development.

We acknowledge the typing skills of Lynn Wesselmann. Contribu- tions to the work upon which much of this review is based were made by Dr. Peter Bechtel and Dr. David DeVol, University of Illinois, Champaign-Urbana; Dr. Michael Chobanian, University of Wisconsin, Madison; Dr. James R. Gavin III, University of Oklahoma, Oklahoma City; and Dr. Jonathan Bortz, Dr. John Mellas, Virginia Hansen, and Sharon Rogers, Washington University, St. Louis, MO. We are especially grateful to Dr. Rosemarie Lajara and Dr. Peter Rotwein, Wash- ington University, for their contributions to studies characterizing IGF I gene expression. We thank those authors who have kindly permitted us to cite their manuscripts that are in press.

M. R. Hammerman was supported by National Institutes of Health Grants DK-27600, and DK-09976 and by Grant 186270 from the Juvenile Diabetes Foundation. This review was written during the tenure of an Established Investigatorship of the American Heart As- sociation.

REFERENCES

ABRASS,~. K.,G.J. RAUGI, L.S. GABOUREL,AND D.H. LOVETT. Insulin and insulin-like growth factor I binding to cultured rat glomerular mesangial cells. Endocrinology 123: 2432-2439, 1988. ALTMAN, P. L., AND D. S. DITTMER. Growth Including Reproduc- tion and Morphological Development. Washington, DC: Federation of American Societies for Experimental Biology, 1962, p. 310-311. ALTSZULER, N. Actions of growth hormone on carbohydrate metabolism. In: Handbook of Physiology. Endocrinology. Washington, DC: Am. Physiol. Sot., 1974, sect. 7, vol. IV, p. 233-252. ANDERSSON, G., AND E. JENNISCHE. IGF-I immunoreactivity is expressed by regenerating renal tubular cells after ischaemic injury in the rat. Actu Physiol Stand. 132: 453-457, 1988.

da.ANDERSSON, G. L., A. SKOTTNER, AND E. JENNISCHE. Immuno- cytochemical and biochemical localization of insulin-like growth factor I in the kidney of rats before and after uninephrectomy. Acta Endocrinol. Copenhagen 119: 555-560,1988.

5. ARNQVIST, H.J.,B.J. BALLERMANN, AND G. L. KING. Receptors

EDITORIAL REVIEW F513

for and effects of insulin and IGF-I in rat glomerular mesangial cells. Am. J. Physiol. 254 (Cell Physiol. 23): C411-C416, 1988.

6. ARON, D. C., J. L. ROSENZWEIG, AND H. A. ABBOUD. Synthesis and binding of insulin-like growth factor I by human glomerular mesangial cells. J. CZin. Endocrinol. Metab. 68: 585-591, 1989.

7. BAXTER, R. C. The insulin-like growth factors and their binding proteins. Comp. Biochem. Physiol. B Comp. Biochem. 91: 229-235, 1988.

8. BORTZ, J. D., P. ROTWEIN, D. DEVOL, P. J. BECHTEL, V. A. HANSEN, AND M. R. HAMMERMAN. Focal expression of insulin- like growth factor I in rat kidney collecting duct. J. Cell BioZ. 107: 811-819,1988.

9. BRISSENDEN, J. E., A. ULLRICH, AND U. FRANCKE. Human chro- mosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor. Nature Lond. 310: 781-784, 1984.

10. BROWN, A. L., D. E. GRAHAM, S. P. NISSLEY, D. J. HILL, A. J. STRAIN, AND M. M. RECHLER. Developmental regulation of insulin-like growth factor II mRNA in different rat tissues. J. BioZ. Chem. 261: 13144-13150,1986.

loa.CAVERZASIO, J., AND J.-P. BONJOUR. Insulin-like growth factor I stimulates Na-dependent Pi transport in cultured kidney cells. Am. J. Physiol. In press.

11. CHAWLA, R. K., J. S. PARKS, AND D. RUDMAN. Structural variants of human growth hormone: biochemical, genetic and clinical as- pects. Annu. Rev. Med. 34: 519-547, 1983.

12. CHOBANIAN, M. C., AND M. R. HAMMERMAN. Insulin stimulates ammoniagenesis in canine renal proximal tubular segments. Am. J. Physiol. 253 (RenaZ Fluid Electrolyte Physiol. 22): F1171-F1177, 1987.

13. CONTI, F. G., L. J. STRIKER, S. J. ELLIOT, D. ANDREANI, AND G. E. STRIKER. Synthesis and release of insulinlike growth factor I by mesangial cells in culture. Am. J. Physiol. 255 (Renal Fluid EZec- trolyte Physiol. 24): F1214-F1219, 1988.

14. CONTI, F. G., L. G. STRIKER, M. A. LESNIAK, K. MACKAY, J. ROTH, AND G. E. STRIKER. Studies on binding and mitogenic effect of insulin and insulin-like growth factor I in glomerular mesangi,al cells. Endocrinology 122: 2788-2795, 1988.

15. CORVILAIN, J., AND M. ABRAMOW. Some effects of human growth hormone on renal hemodynamics and on tubular phosphate transport in man. J. CZin. Inuest. 41: 1230-1235, 1962.

16. CORVILAIN, J., AND M. ABRAMOW. Effect of growth hormone on tubular transport of phosphate in normal and parathyroidectom- ized dogs. J. CZin. Inuest. 43: 1608-1612, 1964.

17. DAUGHADAY, W. H. Growth hormone: normal synthesis, secretion, control, and mechanism of action. In: Endocrinology, edited by L. J. DeGroot. Philadelphia, PA: Saunders, 1989, vol. 1, chapt. 25, p. 318-329.

18. DAUGHADAY, W. H. On the nomenclature of the somatomedins and insulin-like growth factors. Endocrinology 121; 1911-1912, 1987.

19. DE PAGTER-HOLTHUIZEN, P., M. JANSEN, R. A. VAN DER KAM- MEN, F. M. A. VAN SCHAIK, AND J. S. SUSSENBACH. Differential expression of the human insulin-like growth factor II gene. Char- acterization of the IGF-II mRNAs and an mRNA encoding a putative IGF-II-associated protein. Biochim. Biophys. Acta 950: 282-295,1988.

20. D’ERCOLE, A. J. Somatomedins/insulin-like growth factors and fetal growth. J. Deu. Physiol. 9: 481-495, 1987.

21. D’ERCOLE, A. J., G. T. APPLEWHITE, AND L. E. UNDERWOOD. Evidence that somatomedin is synthesized by multiple tissues in the fetus. Deu. BioZ. 75: 315-328, 1980.

22. D’ERCOLE, A. J., C. J. DECEDUE, R. W. FURLANETTO, L. E. UNDERWOOD, AND J. J. VAN WYK. Evidence that somatomedin-C is degraded by the kidney and inhibits insulin degradation. Endo- crinology 101: 577-586, 1977.

23. D’ERCOLE, A. J., D. B. FOUSHEE, AND L. E. UNDERWOOD. Soma- tomedin-C receptor ontogeny and levels in porcine fetal and human cord serum. J. CZin. Endocrinol. Metab. 43: 1069-1077, 1976.

24. D’ERCOLE, A. J., D. J. HILL, A. J. STRAIN, AND L. E. UNDERWOOD. Tissue and plasma somatomedin-C/insulin-like growth factor I concentrations in the human fetus during the first half of gestation. Pediatr. Res. 20: 253-255, 1986.

25. D’ERCOLE, A. J., A. D. STILES, AND L. E. UNDERWOOD. Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action.

Proc. NatZ. Acad. Sci. USA 81: 935-939, 1984. 26. DOI, T., L. J. STRIKER, C. QUAIFE, F. G. CONTI, R. PALMITER, R.

BEHRINGER, R. BRINSTER, AND G. E. STRIKER. Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor but not in those expressing insulin-like growth factor-l. Am. J. Pathol. 131: 398-403,1988.

27. DROP, S. L. S., G. VALIQUETTE, H. J. GUYDA, M. T. CORVOL, AND B. I. POSNER. Partial purification and characterization of a binding protein for insulin-like activity (ILAs) in human amniotic fluid: a possible inhibitor of insulin-like activity. Acta Endocrinol. 90: 505- 518,1979.

28. ELGIN, R. G., W. H. BUSBY, JR., AND D. R. CLEMMONS. An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I. Proc. NatZ. Acad. Sci. USA 84: 3254- 3258,1987.

29. ERICKSON, R. A. Inductive interactions in the development of the mouse metanephros. J. Exp. ZooZ. 169: 33-42, 1968.

30. FAGIN, J. A., AND S. MELMED. Relative increase in insulin-like growth factor I messenger ribonucleic acid levels in compensatory renal hypertrophy. Endocrinology 120: 718-723,1987.

31. FINE, L. The biology of renal hypertrophy. Kidney Int. 29: 619- 634,1986.

32. FLIER, J. S., AND A. C. MOSES. Diabetes in acromegaly and other endocrine disorders. In: Endocrinology, edited by L. J. DeGroot. Philadelphia, PA: Saunders, 1989, chapt. 83, p. 1389-1399.

33. FROESCH, E. R., C. SCHMID, J. SCHWANDER, AND J. ZAPF. Actions of insulin-like growth factors. Annu. Reu. Physiol. 47: 443-467, 1985.

34. GERSHBERG, H., H. 0. HEINEMANN, AND H. H. STUMPF. Renal function studies and autopsy report in a patient with gigantism and acromegaly. J. CZin. Endocrinol. Metab. 17: 377-385, 1957.

35. GOEDDEL, D. V., H. L. HEYNEKER, T. HOZUMI, R. ARENTZEN, K. ITAKURA, D. G. YANSURA, M. J. Ross, G. MIOZZARI, R. CREA, AND P. H. SEEBURG. Direct expression of Escherichia coli of a DNA sequence coding for human growth hormone. Nature Lond. 281: 544-548,1979.

36. GULER, H.-P., C. SCHMID, J. ZAPF, AND E. R. FROESCH. Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proc. NatZ. Acad. Sci. USA 86: 2868-2872,1989.

37. GULER, H.-P., J. ZAPF, E. SCHEIWILLER, AND E. R. FROESCH. Recombinant human insulin-like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc. NatZ. Acad. Sci. USA 85: 4889-4893, 1988.

38. HAMMERMAN, M. R. Insulin-like growth factors and aging. Endo- crinol. Metab. CZin. 16: 995-1011, 1987.

39. HAMMERMAN, M. R., AND J. R. GAVIN, III. Binding of insulin-like growth factor II and multiplication-stimulating activity-stimulated phosphorylation in basolateral membranes from dog kidney. J. BioZ. Chem. 259: 13511-13517,1984.

40. HAMMERMAN, M. R., AND J. R. GAVIN, III. Binding of IGF I and IGF I-stimulated phosphorylation in canine renal basolateral membranes. Am. J. Physiol. 251 (EndocrinoZ. Metab. 14): E32-E41, 1986.

41. HAMMERMAN, M. R., I. E. KARL, AND K. A. HRUSKA. Regulation of canine renal vesicles Pi transport by growth hormone and parathyroid hormone. Biochim. Biophys. Acta 603: 322-335,1980,

42. HAMMERMAN, M. R., AND S. A. ROGERS. Distribution of IGF receptors in the plasma membrane of proximal tubular cells. Am. J. Physiol. 253 (Renal Fluid Electrolyte Physiol. 22): F841-F847, 1987.

43. HAN, V. K. M., A. J. D’ERCOLE, AND P. K. LUND. Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science Wash. DC 236: 193-198,1987.

44. HAN, V. K. M., D. J. HILL, A. J. STRAIN, A. C. TOWLE, J. M. LAUDER, L. E. UNDERWOOD, AND A. J. D’ERCOLE. Identification of somatomedin/insulin-like growth factor immunoreactive cells in the human fetus. Pediatr. Res. 22: 245-247, 1987.

45. HANSSON, H.-A., A. NILSSON, J. ISGAARD, H. BILLIG, 0. ISAKS- SON, A. SKOTTNER, I. K. ANDERSSON, AND B. ROZELL. Immuno- histochemical localization of insulin-like growth factor I in the adult rat. Histochemistry 89: 403-410, 1988.

46. HASELBACHER, G. K., J.-C. IRMINGER, J. ZAPF, W. H. ZIEGLER, AND R. E. HUMBEL. Insulin-like growth factor II in human adrenal


pheochromocytomas and Wilms tumors: expression at the mRNA and protein level. Proc. Natl. Acad. Sci. USA 84: 1104-1106, 1987.

47. HASKELL, J. F., D. J. PILLION, AND E. MEEZAN. Specific, high affinity receptors for insulin-like growth factor II in the rat kidney glomerulus. Endocrinology 123: 774-780, 1988.

48. HIRSCHBERG, R., AND J. D. KOPPLE. Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats. J. Clin. Inuest. 83: 326-330, 1989.

49. HIRSCHBERG, R., H. RABB, R. BERGAMO, AND J. D. KOPPLE. The delayed effect of growth hormone on renal function in humans. Kidney Int. 35: 86%870,1989.

50. HONNEGGER, A., AND T. BLUNDELL. A computer graphics study of insulin-like growth factors and their receptor interactions. In: Insulin-Like Growth Factors. Somatomedins, edited by E. M. Spence. Berlin: de Gruyter, 1983, p. 97-112.

51. HUGHES, J. P. The nature and regulation of the receptors for pituitary growth hormone. Annu. Rev. Physiol. 47: 469-482, 1985.

52. HUSMAN, B., J.-A. GUSTAFSSON, AND G. ANDERSSON. Biogenesis of the somatogenic receptor in rat liver. J. Biol. Chem. 264: 690- 697,1989.

53. JOHNSON, V., AND T. MAACK. Renal extraction, filtration, absorp- tion, and catabolism of growth hormone. Am. J. Physiol. 233 (Renal Fluid Electrolyte Physiol. 2): F185-F196, 1977.

54. JOSEPH, P. K., AND K. SUBRAHMANYAM. Effect of growth hormone, insulin, thyroxine and cortisone on renal gluconeogenesis. Arch. Biochem. Biophys. 127: 288-291,1968.

55. KORNFELD, S. Trafficking of lysosomal enzymes. FASEB J. 1: 462-468,1987.

56. KRIZ, W., AND B. KAISSLING. Structural organization of the mammalian kidney. In: The Kidney: Physiology and Pathophysiology, edited by D. W. Seldin. New York: Raven, 1985, chapt. 14, p. 265- 306.

57. LAJARA, R., P. ROTWEIN, J. D. BORTZ, V. A. HANSEN, J. L. SADOW, C. R. BETTS, S. A. ROGERS, AND M. R. HAMMERMAN. Dual regulation of insulin-like growth factor I expression during renal hypertrophy. Am. J. Physiol. 257 (Renal Fluid Electrolyte Physiol. 26): F252-F261, 1989.

58. LEUNG, D. W., S. A. SPENCER, G. CACHIANES, R. G. HAMMONDS, C. COLLIN, W. J. HENSEL, R. BARNARD, M. J. WATERS, AND W. I. WOOD. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature Lond. 330: 537-543, 1987.

59. MACDONALD, R. G., S. R. PFEFFER, L. COUSSENS, M. A. TEPPER, C. M. BROCKLEBANK, J. E. MOLE, J. K. ANDERSON, E. CHEN, M. P. CZECH, AND A. ULLRICH. A single receptor binds both insulin- like growth factor II and mannose-6-phosphate. Science Wash. DC 239: 1134-1138,1988.

60. MCCONAGHEY, P., AND J. DEHNEL. Preliminary studies of ‘sul- phation factor’ production by rat kidney. J. Endocrinol. 52: 587- 588,1972.

61. MELLAS, J., J. R. GAVIN III, AND M. R. HAMMERMAN. Multipli- cation stimulating activity-induced alkalinization of canine renal proximal tubular cells. J. Biol. Chem. 261: 14437-14442, 1986.

62. MORGAN, DAVID O., J. C. EDMAN, D. N. STANDRING, V. A. FRIED, M. C. SMITH, R. A. ROTH, AND W. J. RUTTER. Insulin-like growth factor II receptor as a multifunctional binding protein. Nature Lond. 329: 301-307, 1987.

63. MURPHY, L. J., G. I. BELL, M. L. DUCKWORTH, AND H. G. FRIESEN. Identification, characterization, and regulation of a rat complementary deoxyribonucleic acid which encodes insulin-like growth factor I. Endocrinology 121: 684-691, 1987.

64. OWENS, P. C., M. W. BRINSTEAD, M. J. WATERS, AND G. D. THORBURN. Ontogenic changes in multiplication-stimulating activity binding to tissues and serum somatomedin-like receptor activity in the ovine fetus. Biochem. Biophys. Res. Commun. 96: 1812-1820,198O.

65. PARVING, H.-H., I. NOER, C. E. MOGENSEN, AND P. A. SVENDSEN. Kidney function in normal man during short-term growth hormone

infusion. Acta Endocrinol. 89: 796-800, 1978. 66. PATTEN, B. M., AND B. M. CARLSON. Foundations of Embryology.

New York: McGraw-Hill, 1974, p. 497-510. 67. PILLION, D. J., J. F. HASKELL, AND E. MEEZAN. Distinct receptors

for insulin-like growth factors I in rat renal glomeruli and tubules. Am. J. Physiol. 255 (Endocrinol. Metab. 12): E504-E512, 1988.

68. QUAIFE, C. J., L. S. MATHEWS, C. A. PINKERT, R. E. HAMMER, R. L. BRINSTER, AND R. D. PALMITER. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124: 40-48, 1989.

69. RABKIN, R., T. I. GOTTHEINER, AND V. S. FANG. Removal and excretion of immunoreactive rat growth hormone by the isolated kidney. Am. J. Physiol. 240 (Renal Fluid Electrolyte Physiol. 9): F282-F287,1981.

70. RECHLER, M. M., AND S. P. NISSLEY. The nature and regulation of the receptors for insulin-like growth factors. Annu. Reu. Physiol. 47: 425-442,1985.

71. REEVE, A. E., M. R. ESSLES, R. J. WILKINS, G. I. BELL, AND L. J. MILLOW. Expression of insulin-like growth factor-II transcripts in Wilms’ tumour. Nature Lond. 317: 258-260,1985.

72. ROGERS, S. A., AND M. R. HAMMERMAN. Insulin-like growth factor II stimulates production of inositol trisphosphate in proximal tubular basolateral membranes from canine kidney. Proc. Natl. Acad. Sci. USA 85: 4037-4041,1988.

73. ROGERS, S. A., AND M. R. HAMMERMAN. Mannose 6-phosphate potentiates insulin-like growth factor II-stimulated inositol trisphosphate production in proximal tubular basolateral membranes. J. Biol. Chem. 264: 4273-4276,1989.

74. ROGERS, S. A., AND M. R. HAMMERMAN. Growth hormone activate phospholipase C in proximal tubular basolateral membranes from canine kidney. Proc. NatZ. Acad. Sci. USA. 86: 6363-6366,1989.

75. ROGERS, S. A., AND M. R. HAMMERMAN. Growth hormone directly stimulates gluconeogenesis in canine renal proximal tubule. Am. J. Physiol. 257 (Endocrinol. Metab. 20), 1989.

76. ROTH, R. A. Structure of the receptor for insulin-like growth factor II: The puzzle amplified. Science Wash. DC 239: 1269-1271,1988.

77. ROTWEIN, P., K. M. POLLOCK, D. K. DIDIER, AND G. G. KRIVI. Organization and sequence of the human insulin-like growth factor I gene. J. Biol. Chem. 261: 4828-4832, 1986.

78. ROTWEIN, P., K. M. POLLOCK, M. WATSON, AND J. D. MIL- BRANDT. Insulin-like growth factor gene expression during rat embryonic development. Endocrinology 121: 2141-2144, 1987.

79. SALMON, W. D., AND W. H. DAUGHADAY. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J. Lab. Clin. Med. 49: 825-836, 1957.

80. SCOTT, J., J. COWELL, M. E. ROBERTSON, L. M. PRIESTLEY, R. WADEY, B. HOPKINS, J. PRITCHARD, G. I. BELL, L. B. RALL, C. F. GRAHAM, AND T. J. KNOTT. Insulin-like growth factor-II gene expression in Wilms’ tumour and embryonic tissues. Nature Lond. 317: 260-262,1985.

81. STILES, A. D, I. R. S. SOSENKO, A. J. D’ERCOLE, AND B. T. SMITH. Relation of kidney tissue somatomedin-C/insulin-like growth factor I to postnephrectomy renal growth in the rat. En- docrinology 117: 2397-2401, 1985.

82. TRICOLI, J. V., L. B. RALL, J. SCOTT, G. I. BELL, AND T. B. SHOWS. Localization of insulin-like growth factor genes to human chromosomes 11 and 12. Nature Lond. 310: 784-786,1984.

83. VALENTINO, K. L., H. PHAM, I. OCRANT, AND R. G. ROSENFELD. Distribution of insulin-like growth factor II receptor immunoreactivity in rat tissues. Endocrinology 122: 2753-2763, 1988.

84. WALLIS, M. The molecular evolution of pituitary growth hormone prolactin and placental lactogen: a protein family showing variable rates of evolution. J. Mol. EuoZ. 17: 10-18, 1981.

85. YEE, D., S. PAIK, G. S. LEBOIC, R. R. MARCUS, R. E. FAVONI, K. J. CULLEN, M. E. LIPPMAN, AND N. ROSEN. Analysis of insulin- like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol. EndocrinoZ. 3: 509- 517,1989.

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Hammerman AJP 1989 GHIGF1 Axis