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The expression of growth-arrest genes in the liver and kidney of the protein-restricted rat fetus

  • Christopher A. Maloney (a1), Christina Lilley (a1), Morven Cruickshank (a1), Caroline McKinnon (a1), Susan M. Hay (a1) and William D. Rees (a1)...


During fetal life, there are periods of rapid cell proliferation, which are uniquely sensitive to nutritional perturbation. Feeding the pregnant rat a protein-restricted diet alters the growth trajectory of major fetal organs such as the kidney. By day 21 of gestation, the ratio of kidney weight to total body weight is reduced in the fetuses of dams fed a protein-deficient diet. In contrast, the ratio of fetal liver weight to total body weight is unchanged. To investigate the mechanisms underlying this disproportionate change in organ growth in the low-protein group, cell proliferation and differentiation have been assessed in the liver and kidney. The steady-state levels of mRNA for the growth-arrest and DNA-damage gene gadd153/CHOP-10, CCAAT enhancer-binding proteins α and β were unaffected by maternal diet in both fetal liver and kidney. The mRNA for alpha-fetoprotein, albumin and hepatic glucokinase were unchanged in the liver, suggesting that maternal protein deficiency does not alter the state of differentiation. The steady-state levels of the mRNA coding for the cyclin-dependent protein kinase inhibitors (p15INK4a, p19INK4d, p21CIP1, p27KIP1 and p57KIP2) were unchanged in the fetal livers but were significantly increased in the kidneys of fetuses from dams fed the low-protein diet. These results show that the asymmetrical growth of the kidney is associated with increases in mRNA for the Cip/Kip cyclin-dependent kinase inhibitors and that these may reflect specific lesions in organ development.

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Corresponding author

*Corresponding author: Dr William D. Rees, fax +44 (0) 1224 715349, email


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Barker, DJ & Osmond, C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1, 10771081.
Bogdarina, I, Murphy, HC, Burns, SP & Clark, AJ (2004) Investigation of the role of epigenetic modification of the rat glucokinase gene in fetal programming. Life Sci 74, 14071415.
Burns, SP, Desai, M, Cohen, RD, Hales, CN, Iles, RA, Germain, JP, Going, TC & Bailey, RA (1997) Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest 100, 17681774.
Canavan, JP & Goldspink, DF (1988) Maternal diabetes in rats II. Effects on fetal growth and protein turnover. Diabetes 37, 16711677.
Desai, M, Crowther, NJ, Ozanne, SE, Lucas, A & Hales, CN (1995) Adult glucose and lipid metabolism may be programmed during fetal life. Biochem Soc Trans 23, 331335.
El Khattabi, I, Gregoire, F, Remacle, C & Reusens, B (2003) Isocaloric maternal low-protein diet alters IGF-I, IGFBPs, and hepatocyte proliferation in the fetal rat. Am J Physiol Endocrinol Metab 285, E991E1000.
Fleming, JV, Hay, SM, Harries, DN & Rees, WD (1998) Effects of nutrient deprivation and differentiation on the expression of growth-arrest genes (gas and gadd) in F9 embryonal carcinoma cells. Biochem J 330, Part 1, 573579.
Gluckman, PD & Hanson, MA (2004) The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 15, 183187.
Gruppuso, PA, Bienieki, TC & Faris, RA (1999) The relationship between differentiation and proliferation in late gestation fetal rat hepatocytes. Pediatr Res 46, 1419.
Hales, CN & Barker, DJ (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595601.
Hiromura, K, Haseley, LA, Zhang, P, Monkawa, T, Durvasula, R, Petermann, AT, Alpers, CE, Mundel, P & Shankland, SJ (2001) Podocyte expression of the CDK-inhibitor p57 during development and disease. Kidney Int 60, 22352246.
Huang, DP, Cote, GJ, Massari, RJ & Chiu, JF (1985) Dexamethasone inhibits alpha-fetoprotein gene transcription in neonatal rat liver and isolated nuclei. Nucleic Acids Res 13, 38733890.
Ilyin, GP, Glaise, D, Gilot, D, Baffet, G & Guguen-Guillouzo, C (2003) Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth. Am J Physiol Gastrointest Liver Physiol 285, G115G127.
Kato, JY, Matsuoka, M, Polyak, K, Massague, J & Sherr, CJ (1994) Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell 79, 487496.
Langley, SC & Jackson, AA (1994) Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin Sci (Colch) 86, 217222.
Langley-Evans, SC (1997) Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. J Hypertens 15, 537544.
Langley-Evans, SC, Gardner, DS & Jackson, AA (1996) Association of disproportionate growth of fetal rats in late gestation with raised systolic blood pressure in later life. J Reprod Fertil 106, 307312.
Langley-Evans, SC & Jackson, AA (1996) Rats with hypertension induced by in utero exposure to maternal low-protein diets fail to increase blood pressure in response to a high salt intake. Ann Nutr Metab 40, 19.
Langley-Evans, SC, Welham, SJ & Jackson, AA (1999) Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci 64, 965974.
Liao, WS, Conn, AR & Taylor, JM (1980) Changes in rat alpha 1-fetoprotein and albumin mRNA levels during fetal and neonatal development. J Biol Chem 255, 1003610039.
McMullen, S, Gardner, DS & Langley-Evans, SC (2004) Prenatal programming of angiotensin II type 2 receptor expression in the rat. Br J Nutr 91, 133140.
Nahon, JL, Tratner, I, Poliard, A, Presse, F, Poiret, M, Gal, A, Sala-Trepat, JM, Legres, L, Feldmann, G & Bernuau, D (1988) Albumin and alpha-fetoprotein gene expression in various nonhepatic rat tissues. J Biol Chem 263, 1143611442.
Ramji, DP & Foka, P (2002) CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 365, 561575.
Rees, WD, Hay, SM, Buchan, V, Antipatis, C & Palmer, RM (1999) The effects of maternal protein restriction on the growth of the rat fetus and its amino acid supply. Br J Nutr 81, 243250.
Rees, WD, Hay, SM, Palmer, RM & Antipatis, C (2000) Maternal protein deficiency alters the fetal growth trajectory during late gestation. Proc Nut Soc 59, 62A.
Rees, WD, Prins, ME & Hay, SM (2003) Gene nutrient interactions as a result of amino acid deficiency; effect on mRNAs associated with the cell cycle. EAAP Scientific Series:, Prog Res Energ Prot Metab 109, 6972.
Sakamoto, I, Takahashi, T, Kakita, A, Hayashi, I, Majima, M & Yamashina, S (2002) Experimental study on hepatic reinnervation after orthotopic liver transplantation in rats. J Hepatol 37, 814823.
Seto, M, Kim, S, Yoshifusa, H, Nakamura, Y, Masuda, T, Hamaguchi, A, Yamanaka, S & Iwao, H (1998) Effects of prednisolone on glomerular signal transduction cascades in experimental glomerulonephritis. J Am Soc Nephrol 9, 13671376.
Shankland, SJ, Eitner, F, Hudkins, KL, Goodpaster, T, D'Agati, V & Alpers, CE (2000) Differential expression of cyclin-dependent kinase inhibitors in human glomerular disease: role in podocyte proliferation and maturation. Kidney Int 58, 674683.
Shankland, SJ & Wolf, G (2000) Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. Am J Physiol Renal Physiol 278, F515F529.
Sherr, CJ & Roberts, JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9, 11491163.
Snoeck, A, Remacle, C, Reusens, B & Hoet, JJ (1990) Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol Neonate 57, 107118.
Staels, B & Auwerx, J (1992) Perturbation of developmental gene expression in rat liver by fibric acid derivatives: lipoprotein lipase and alpha-fetoprotein as models. Development 115, 10351043.
Terada, Y, Inoshita, S, Nakashima, O, Kuwahara, M, Sasaki, S & Marumo, F (1998) Cyclins and the cyclin-kinase system – their potential roles in nephrology. Nephrol Dial Transplant 13, 19131916.
Terada, Y, Okado, T, Inoshita, S, Hanada, S, Kuwahara, M, Sasaki, S, Yamamoto, T & Marumo, F (2001) Glucocorticoids stimulate p21(CIP1) in mesangial cells and in anti-GBM glomerulonephritis. Kidney Int 59, 17061716.
Westbury, J, Watkins, M, Ferguson-Smith, AC & Smith, J (2001) Dynamic temporal and spatial regulation of the cdk inhibitor p57(kip2) during embryo morphogenesis. Mech Dev 109, 8389.
Widdowson, EM (1971) Intra-uterine growth retardation in the pig I. Organ size and cellular development at birth and after growth to maturity. Biol Neonate 19, 329340.
Wintour, EM, Johnson, K, Koukoulas, I, Moritz, K, Tersteeg, M & Dodic, M (2003) Programming the cardiovascular system, kidney and the brain – a review. Placenta 24, Suppl A, S65S71.
Wolf, G, Wenzel, U, Hannken, T & Stahl, RA (2001) Angiotensin II induces p27(Kip1) expression in renal tubules in vivo: role of reactive oxygen species. J Mol Med 79, 382389.
Woods, LL, Weeks, DA & Rasch, R (2004) Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Int 65, 13391348.
Zhang, P, Liegeois, NJ & Wong, C (1997) Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith–Wiedemann syndrome. Nature 387, 151158.



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