Abstract

Children with chronic renal failure (CRF) grow poorly; the CRF state interferes with the hormonal control of linear growth, and may interfere with the general function of specific growth factors. Growth hormone (GH) and insulin-like growth factor (IGF)-I promote linear growth by synergistically stimulating mitogenic pathways in growth-plate chondrocytes. GH and IGF-I levels are normal in CRF serum, and IGF-I is bioactive. However, CRF serum contains an excess of proteins, the IGF binding proteins (IGFBPs), which can compete with cell-surface receptors for IGF-I binding and in this way inhibit IGF-I action. Two specific IGFBPs (IGFBP-1 and a 33 kiloDalton or kD IGFBP), and perhaps a third (IGFBP-3), contribute to this CRF pool of proteins which bind free IGF-I. IGFBP-1 is clearly, and the 33 kD IGFBP is probably, a potent inhibitor of IGF-I action in vitro. The overall objective of this proposal is to study the role of IGFBPs as IGF-I inhibitors in CRF; it is anticipated that this work will suggest (i) which IGFBPs inhibit linear growth, and (ii) how to reverse the inhibition. Specific antisera will determine if the 33 kD IGFBP is IGFBP-2, a potent IGF-I inhibitor. Specific antisera, gel filtration, and (125)I-IGF-I binding studies will also (i) determine the size and bioactivity of a potentially growth-stimulating IGFBP (IGFBP-3) found in excess in CRF serum by RIA; and (ii) characterize IGFBPs in peritoneal dialysate, since this will indicate which IGFBPs are in the extravascular space and are thus able to inhibit IGF-I acting by paracrine or autocrine mechanisms. Children entered in a multicenter trial of GH therapy for CRF-related growth failure will also be studied. Changes in serum IGFBP profiles will be related to growth response and whether GH was givnen; it is anticipated that levels of inhibitory IGFBPs (e.g. IGFBP-1) will fall with GH and improved growth. Effects of IGFBPs on growth and growth-plate cartilage in vivo will be tested by treating growing rats with IGFBPs purified from cultured cells or by overexpression of cloned IGFBP genes. Finally, the mechanism behind high IGFBP levels in CRF will be studied by measuring IGFBP mRNA levels in a rat CRF model, and by studying the effect of purported low MW inhibitors of IGF-I action on a tissue culture model of hepatic IGFBP-1 production.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038773-07
Application #
3238275
Study Section
General Medicine B Study Section (GMB)
Project Start
1986-09-01
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Kiepe, Daniela; Ulinski, Tim; Powell, David R et al. (2002) Differential effects of insulin-like growth factor binding proteins-1, -2, -3, and -6 on cultured growth plate chondrocytes. Kidney Int 62:1591-600
Modric, T; Silha, J V; Shi, Z et al. (2001) Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice. Endocrinology 142:1958-67
Scheimann, A O; Durham, S K; Suwanichkul, A et al. (2001) Role of three FKHR phosphorylation sites in insulin inhibition of FKHR action in hepatocytes. Horm Metab Res 33:631-8
Silha, J V; Gui, Y; Modric, T et al. (2001) Overexpression of the acid-labile subunit of the IGF ternary complex in transgenic mice. Endocrinology 142:4305-13
Conover, C A; Bale, L K; Durham, S K et al. (2000) Insulin-like growth factor (IGF) binding protein-3 potentiation of IGF action is mediated through the phosphatidylinositol-3-kinase pathway and is associated with alteration in protein kinase B/AKT sensitivity. Endocrinology 141:3098-103
Powell, D R; Liu, F; Baker, B K et al. (2000) Effect of chronic renal failure and growth hormone therapy on the insulin-like growth factors and their binding proteins. Pediatr Nephrol 14:579-83
Suwanichkul, A; Boisclair, Y R; Olney, R C et al. (2000) Conservation of a growth hormone-responsive promoter element in the human and mouse acid-labile subunit genes. Endocrinology 141:833-8
Durham, S K; Suwanichkul, A; Scheimann, A O et al. (1999) FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. Endocrinology 140:3140-6
Durham, S K; Suwanichkul, A; Hayes, J D et al. (1999) The heparin binding domain of insulin-like growth factor binding protein (IGFBP)-3 increases susceptibility of IGFBP-3 to proteolysis. Horm Metab Res 31:216-25
Campbell, P G; Durham, S K; Hayes, J D et al. (1999) Insulin-like growth factor-binding protein-3 binds fibrinogen and fibrin. J Biol Chem 274:30215-21

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