Growth Factor Production

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Production of epidermal growth factor (EGF), insulin-like growth factor (IGF-I), and hepatocyte growth factor (HGF) by various tissues. EGF, IGF-I, and HGF have all been demonstrated to improve outcomes in various animal models of acute renal failure (ARF). All three growth-promoting factors are produced in the kidneys and in a variety of other organs. The local production is probably most important for recovery from an acute renal insult. The influence of production in other organs in the setting of ARF has yet to be determined. This chapter deals primarily with local production and actions of EGF, IGF-I, and HGF.

FIGURE 17-6

Receptor binding for epidermal growth factor (EGF). EGF binding in kidney under basal conditions is extensive. The most significant specific binding occurs in the proximal convoluted (PCT) and proximal straight tubules. There is also significant EGF binding in the glomeruli (GLOM), distal convoluted tubules (DCT), and the entire collecting duct (OMCD, IMCD). After an ischemic renal insult, EGF receptor numbers increase. This change in the renal EGF system may be responsible for the beneficial effect of exoge-nously administered EGF is the setting of acute renal failure. CTAL—cortical thick ascending loop.

MAPKK ERK1/ERK2 Gene transcription Growth differentiation

MAPKK ERK1/ERK2 Gene transcription Growth differentiation

FIGURE 17-7

Epidermal growth factor (EGF)-mediated signal transduction pathways. The EGF receptor triggers the phospholipase C-gamma (PLC-gamma), phosphatidylinositol-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) signal transduction pathways described in the text that follows.

Growth factors exert their downstream effects through their plasma membrane-bound protein tyrosine kinase (PTK) receptors. All known PTK receptors are found to have four major domains: 1) a glycosylated extracellular ligand-binding domain; 2) a transmembrane domain that anchors the receptor to the plasma membrane; 3) an intracellular tyrosine kinase domain; and 4) regulatory domains for the PTK activity. Upon ligand binding, the receptors dimerize and autophosphorylate, which leads to a cascade of intracellular events resulting in cellular proliferation, differentiation, and survival.

The tyrosine phosphorylated residues in the cytoplasmic domain of PTK are of utmost importance for its interactions with cytoplasmic proteins involved in EGF-mediated signal transduction pathways. The interactions of cytoplasmic proteins are governed by specific domains termed Src homology type 2 (SH2) and type 3 (SH3) domains. The SH2 domain is a conserved 100-amino acid sequence initially characterized in the PTK-Src and binds to tyrosine phosphorylated motifs in proteins; the SH3 domain binds to their targets through proline-rich sequences. SH2 domains have been found in a multitude of signal transducers and docking proteins such as growth factor receptor-bound protein 2 (Grb2), phophatidy-linositol-3 kinase (p85-Pl3K), phospholipase C-gamma (PLC-gamma), guanosine triphosphatase (GTPase)-activating protein of ras (ras-GAP), and signal transducer and activator of transcription 3 (STAT-3).

Upon ligand binding and phosphorylation of PTKs, SH2-domain containing proteins interact with the receptor kinase domain. PLC-gamma on interaction with the PTK, becomes phosphorylated and catalyzes the turnover of phosphatidylinositol (PIP2) to two other second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG).

DAG activates protein kinase C; IP3 raises the intracellular calcium (Ca2+) levels by inducing its release from intracellular stores. Ca2+ is involved in the activation of the calmodulin-dependent CAM-kinase, which is a serine/threonine kinase.

A more important signal transduction pathway activated by PTKs concerns the ras pathway. The ras cycle is connected to activated receptors via the adapter protein Grb2 and the guanosine diphosphate-guanosine triphosphate exchange factor Sos (son of sevenless). GDP-ras, upon phospho-rylation, is converted to its activated form, GTP-ras. The activated ras activates another Ser/Thr kinase called raf-1, which in turn activates another kinase, the mitogen activated protein kinase kinase (MAPKK). MAPKK activates the serine/threonine kinases, and extracellular signal-regulated kinases Erkl and 2. Activation of Erk1/2 leads to translocation into the nucleus, where it phosphorylates key transcription factors such as Elk-1, and c-myc. Phosphorylated Elk-1 associates with serum response factor (SRF) and activates transcription of c-fos. The protein products of c-fos and c-jun function cooperatively as components of the mammalian transcription factor AP-1. AP-1 binds to specific DNA sequences in putative promoter sequences of target genes and regulates gene transcription. Similarly, c-myc forms a het-erodimer with another immediate early gene max and regulates transcription.

The expression of c-fos, c-jun, and Egr-1 is found to be upregulated after ischemic renal injury. Immunohistochemical analysis showed the spatial expression of c-fos and Egr-1 to be in thick ascending limbs, where cells are undergoing minimal proliferation as compared with the S3 segments of the proximal tubules. This may suggest that the expression of immediate early genes after ischemic injury is not associated with cell proliferation.

Several mechanisms control the specificity of RTK signaling: 1) the specific ligand-receptor interaction; 2) the repertoire of substrates and signaling molecules associated with the activated RTK; 3) the existence of tissue-specific signaling molecules; and 4) the apparent strength and persistence of the biochemical signal. Interplay of these factors can determine whether a given ligand-receptor interaction lead to events such as growth, differentiation, scatter or survival.

FIGURE 17-8

FIGURE 17-9

FIGURE 17-8

Expression of mRNA for insulin-like growth factor I (IGF-I). Under basal conditions, a variety of nephron segments can produce IGF-I. Glomeruli (GLOM), medullary and cortical thick ascending limbs (MTAL/CTAL), and collecting ducts (OMCD, IMCD) are all reported to produce IGF-I. Within hours of an acute ischemic renal insult, the expression of IGF-I decreases; however, 2 to 3 days after the insult, when there is intense regeneration, there is an increase in the expression of IGF-I in the regenerative cells. In addition, extratubule cells, predominantly macrophages, express IGF-I in the regenerative period. This suggests that IGF-I works by both autocrine and paracrine mechanisms during the regenerative process. DCT/PCT—distal/proximal convoluted tubule.

FIGURE 17-9

Receptor binding for insulin-like growth factor I (IGF-I). IGF-I binding sites are conspicuous throughout the normal kidney. Binding is higher in the structures of the inner medulla than in the cortex. After an acute ischemic insult, there is a marked increase in IGF-I binding throughout the kidney. The increase appears to be greatest in the regenerative zones, which include structures of the cortex and outer medulla. These findings suggest an important trophic effect of IGF-I in the setting of acute renal injury. CTAL/MTAL—cortical/medullary thick ascending loop; DCT/PCT—distal/proximal convoluted tubule; GLOM—glomerulus; OMCD/IMCD—outer/inner medullary collecting duct.

Olympus Endoscopy System

FIGURE 17-10

Diagram of intracellular signaling pathways mediated by the insulin-like growth factor I (IGF-IR) receptor. IGF-IR when bound to IGF-I undergoes autophosphorylation on its tyrosine residues. This enhances its intrinsic tyrosine kinase activity and phosphorylates multiple substrates, including insulin receptor substrate 1 (IRS-1), IRS-2, and Src homology/collagen (SHC). IRS-1 upon phosphorylation associates with the p85 subunit of the PI3-kinase (PI3K) and phos-phorylates PI3-kinase. PI3K upon phospho-rylation converts phosphoinositide-3 phosphate (PI-3P) into PI-3,4-P2, which in turn activates a serine-thronine kinase Akt (protein kinase B). Activated Akt kinase phos-phorylates the proapoptotic factor Bad on a serine residue, resulting in its dissociation from B-cell lymphoma-X (Bc1-Xl) . The released Bc1-Xl is then capable of suppressing cell death pathways that involve the activity of apoptosis protease activating factor (Apaf-1), cytochrome C, and caspases. A number of growth factors, including platelet-derived growth factor (PDGF) and IGF 1 promotes cell survival. Activation of the PI3K cascade is one of the mechanisms by which growth factors mediate cell survival. Phosphorylated IRS-1 also associates with growth factor receptor bound protein 2 (Grb2), which bind son of sevenless (Sos) and activates the ras-raf-mitogen activated protein (ras/raf-MAP) kinase cascade. SHC also binds Grb2/Sos and activates the ras/raf-MAP kinase cascade. Other substrates for IGF-I are phosphotyrosine phos-phatases and SH2 domain containing tyro-sine phosphatase (Syp). Figure 17-7 has details on the other signaling pathways in this figure. MBP—myelin basic protein; nck—an adaptor protein composed of SH2 and SH3 domains; TF—transcription factor.

Expression of hepatocyte growth factor (HGF) mRNA and HGF receptor mRNA in kidney. While the liver is the major source of circulating HGF, the kidney also produces this growth-promoting peptide. Experiments utilizing in situ hybridization, immunohisto-chemistry, and reverse transcription-polymerase chain reaction (RT-PCR) have demonstrated HGF production by interstitial cells but not by any nephron segment. Presumably, these interstitial cells are macrophages and endothelial cells. Importantly, HGF expression in kidney actually increases within hours of an ischemic or toxic insult. This expression peaks within 6 to 12 hours and is followed a short time later by an increase in HGF bioactivity. HGF thus seems to act as a renotrophic factor, participating in regeneration via a paracrine mechanism; however, its expression is also rapidly induced in spleen and lung in animal models of acute renal injury. Reported levels of circulating HGF in patients with acute renal failure suggest that an endocrine mechanism may also be operational.

The receptor for HGF is the c-met proto-oncogene product. Receptor binding has been demonstrated in kidney in a variety of sites, including the proximal convoluted (PCT) and straight tubules, medullary and cortical thick ascending limbs (MTAL, CTAL), and in the outer and inner medullary collecting ducts (OMCD, IMCD). As with HGF peptide production, expression of c-met mRNA is induced by acute renal injury.

Membrane bound Pro-HGF

Matrix soluble pro-HGF

Membrane bound Pro-HGF

Matrix soluble pro-HGF

Hgf Cmet Myelin

FIGURE 17-12

Model of hepatocyte growth factor (HGF)/c-met signal transduction. In the extracellular space, single-chain precursors of HGF bound to the proteoglycans at the cell surface are converted to the active form by urokinase plasminogen activator (uPA), while the matrix soluble precursor is processed by a serum derived pro-HGF convertase. HGF, upon binding to its receptor c-met, induces its dimerization as well as autophosphorylation of tyrosine residues. The phosphorylated residue binds to various adaptors and signal transducers such as growth factor receptor bound pro-tein-2 (Grb2), p85-PI3 kinase, phospholi-pase C-gamma (PLC-gamma), signal transducer and activator of transcription-3 (STAT-3) and Src homology/collagen (SHC) via Src homology 2 (SH2) domains and triggers various signal transduction pathways. A common theme among tyrosine kinase receptors is that phosphorylation of different specific tyrosine residues determines which intracellular transducer will bind the receptor and be activated. In the case of HGF receptor, phosphorylation of a single multifunctional site triggers a pleiotropic response involving multiple signal transducers. The synchronous activation of several signaling pathways is essential to conferring the distinct invasive growth ability of the HGF receptor. HGF functions as a scattering (dissociation/motility) factor for epithelial cells, and this ability seems to be mediated through the activation of STAT-3.

Phosphorylation of adhesion complex regulatory proteins such as ZO-1, beta-catenin, and focal adhesion kinase (FAK) may occur via activation of c-src. Another Bcl2 interacting protein termed BAG-1 mediates the antiapoptotic signal of HGF receptor by a mechanism of receptor association independent from tyrosine residues.

Mitogenic

Anabolic

Morphogenic

Alter leukocyte function

Cell migration

Alter inflammatory process

Hemodynamic

Apoptosis

Cytoprotective

Others

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