Hostname: page-component-848d4c4894-cjp7w Total loading time: 0 Render date: 2024-06-25T05:30:42.689Z Has data issue: false hasContentIssue false

Maternal undernutrition results in altered renal pro-inflammatory gene expression concomitant with hypertension in adult male offspring that is ameliorated following pre-weaning growth hormone treatment

Published online by Cambridge University Press:  17 December 2018

X. D. Zhang
Liggins Institute, University of Auckland, Auckland, New Zealand
C. M. Reynolds
Liggins Institute, University of Auckland, Auckland, New Zealand
C. Gray
Liggins Institute, University of Auckland, Auckland, New Zealand
M. Li
Liggins Institute, University of Auckland, Auckland, New Zealand
M. H. Vickers*
Liggins Institute, University of Auckland, Auckland, New Zealand
Address for correspondence: Professor Mark Vickers, Liggins Institute, University of Auckland, Auckland 1142, New Zealand. E-mail:


An adverse early life environment is associated with increased cardiovascular disease in offspring. Work in animal models has shown that maternal undernutrition (UN) during pregnancy leads to hypertension in adult offspring, with effects thought to be mediated in part via altered renal function. We have previously shown that growth hormone (GH) treatment of UN offspring during the pre-weaning period can prevent the later development of cardiometabolic disorders. However, the mechanistic basis for these observations is not well defined. The present study examined the impact of GH treatment on renal inflammatory markers in adult male offspring as a potential mediator of these reversal effects. Female Sprague-Dawley rats were fed either a chow diet fed ad libitum (CON) or at 50% of CON intake (UN) during pregnancy. All dams were fed the chow diet ad libitum during lactation. CON and UN pups received saline (CON-S/UN-S) or GH (2.5 µg/g/day; CON-GH/UN-GH) from postnatal day 3 until weaning (p21). Post-weaning males were fed a standard chow diet for the remainder of the study (150 days). Histological analysis was performed to examine renal morphological characteristics, and gene expression of inflammatory and vascular markers were assessed. There was evidence of renal hypotrophy and reduced nephron number in the UN-S group. Tumour necrosis factor-α, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 gene expression was increased in UN-S offspring and normalized in the UN-GH group. These findings indicate that pre-weaning GH treatment has the potential to normalize some of the adverse renal and cardiovascular sequelae that arise as a consequence of poor maternal nutrition.

Original Article
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Brenseke, B, Prater, MR, Bahamonde, J, Gutierrez, JC. Current thoughts on maternal nutrition and fetal programming of the metabolic syndrome. J Pregnancy. 2013; 2013, 368461.CrossRefGoogle ScholarPubMed
Gluckman, PD, Hanson, MA, Beedle, AS, Spencer, HG. Predictive adaptive responses in perspective. Trends Endocrinol Metab. 2008; 19, 109110.CrossRefGoogle Scholar
Hales, CN, Barker, DJ. The thrifty phenotype hypothesis. Br Med Bull. 2001; 60, 520.CrossRefGoogle ScholarPubMed
Barker, DJ, Osmond, C, Golding, J, Kuh, D, Wadsworth, ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989; 298, 564567.Google Scholar
Wadhwa, PD, Buss, C, Entringer, S, Swanson, JM. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med. 2009; 27, 358368.CrossRefGoogle ScholarPubMed
Hoppe, CC, Evans, RG, Moritz, KM, et al. Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure. Am J Physiol Regul Integr Comp Physiol. 2007; 292, R462R469.CrossRefGoogle ScholarPubMed
Wintour, EM, Moritz, KM, Johnson, K, et al. Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol. 2003; 549, 929935.CrossRefGoogle ScholarPubMed
Luyckx, VA, Brenner, BM. Low birth weight, nephron number, and kidney disease. Kidney Int Suppl. 2005; 97, S68S77.CrossRefGoogle Scholar
Langley-Evans, SC, Sherman, RC, Welham, SJ, et al. Intrauterine programming of hypertension: the role of the renin-angiotensin system. Biochem Soc Trans. 1999; 27, 8893.CrossRefGoogle ScholarPubMed
Rasch, R, Skriver, E, Woods, LL. The role of the RAS in programming of adult hypertension. Acta Physiol Scand. 2004; 181, 537542.CrossRefGoogle ScholarPubMed
Richter, VF, Briffa, JF, Moritz, KM, Wlodek, ME, Hryciw, DH. The role of maternal nutrition, metabolic function and the placenta in developmental programming of renal dysfunction. Clin Exp Pharmacol Physiol. 2016; 43, 135141.CrossRefGoogle ScholarPubMed
Segovia, SA, Vickers, MH, Gray, C, Reynolds, CM. Maternal obesity, inflammation, and developmental programming. Biomed Res Int. 2014; 418975.Google ScholarPubMed
Stewart, T, Jung, FF, Manning, J, Vehaskari, VM. Kidney immune cell infiltration and oxidative stress contribute to prenatally programmed hypertension. Kidney Int. 2005; 68, 21802188.CrossRefGoogle ScholarPubMed
Gray, C, Li, M, Reynolds, CM, Vickers, MH. Pre-Weaning Growth Hormone Treatment Reverses Hypertension and Endothelial Dysfunction in Adult Male Offspring of Mothers Undernourished during Pregnancy. PLoS ONE. 2013; 8, e53505.CrossRefGoogle ScholarPubMed
Gray, C, Li, M, Reynolds, CM, Vickers, MH. Let-7 miRNA profiles are associated with the reversal of left ventricular hypertrophy and hypertension in adult male offspring from mothers undernourished during pregnancy following pre-weaning growth hormone treatment. Endocrinology. 2014; 155, 48084817.CrossRefGoogle Scholar
Reynolds, CM, Li, M, Gray, C, Vickers, MH. Pre-weaning Growth Hormone Treatment Ameliorates Adipose Tissue Insulin Resistance and Inflammation in Adult Male Offspring Following Maternal Undernutrition. Endocrinology. 2013; 154(8), 26762686.CrossRefGoogle Scholar
Reynolds, CM, Li, M, Gray, C, Vickers, MH. Pre-Weaning Growth Hormone Treatment Ameliorates Bone Marrow Macrophage Inflammation in Adult Male Rat Offspring following Maternal Undernutrition. PLoS ONE. 2013; 8, e68262.CrossRefGoogle ScholarPubMed
Hammerman, MR, Miller, SB. Effects of growth hormone and insulin-like growth factor I on renal growth and function. J Pediatr. 1997; 131, S17S19.CrossRefGoogle ScholarPubMed
Koch, JM, Wilmoth, TA, Wilson, ME. Periconceptional growth hormone treatment alters fetal growth and development in lambs. J Anim Sci. 2010; 88, 16191625.CrossRefGoogle ScholarPubMed
Setia, S, Sridhar, MG. Changes in GH/IGF-1 axis in intrauterine growth retardation: consequences of fetal programming? Horm Metab Res. 2009; 41, 791798.CrossRefGoogle ScholarPubMed
Brennan, KA, Olson, DM, Symonds, ME. Maternal nutrient restriction alters renal development and blood pressure regulation of the offspring. Proc Nutr Soc. 2006; 65, 116124.CrossRefGoogle ScholarPubMed
Hammerman, MR, Miller, SB. The growth hormone insulin-like growth factor axis in kidney revisited. Am J Physiol. 1993; 265, F1F14.Google ScholarPubMed
Kamenicky, P, Mazziotti, G, Lombes, M, Giustina, A, Chanson, P. Growth hormone, insulin-like growth factor-1, and the kidney: pathophysiological and clinical implications. Endocr Rev. 2014; 35, 234281, P.CrossRefGoogle ScholarPubMed
Hirschberg, R. Effects of growth hormone and IGF-I on glomerular ultrafiltration in growth hormone-deficient rats. Regul Pept. 1993; 48, 241250.CrossRefGoogle ScholarPubMed
Palmeiro, CR, Anand, R, Dardi, IK, et al. Growth hormone and the cardiovascular system. Cardiol Rev. 2012; 20, 197207.CrossRefGoogle ScholarPubMed
Lombardi, G, Di Somma, C, Grasso, LF, et al. The cardiovascular system in growth hormone excess and growth hormone deficiency. J Endocrinol Invest. 2012; 35, 10211029.Google ScholarPubMed
Schmittgen, TD, Livak, KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3, 11011108.CrossRefGoogle Scholar
Huang, L, Haylor, JL, Hau, Z, et al. Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney Int. 2009; 76, 383394.CrossRefGoogle ScholarPubMed
Li, M, Reynolds, CM, Gray, C, Vickers, MH. Preweaning GH Treatment Normalizes Body Growth Trajectory and Reverses Metabolic Dysregulation in Adult Offspring After Maternal Undernutrition. Endocrinology. 2015; 156, 32283238.CrossRefGoogle ScholarPubMed
Landgraf, MA, Martinez, LL, Rastelli, VM, et al. Intrauterine undernutrition in rats interferes with leukocyte migration, decreasing adhesion molecule expression in leukocytes and endothelial cells. J Nutr. 2005; 135, 14801485.CrossRefGoogle ScholarPubMed
Khraibi, AA. Association between disturbances in the immune system and hypertension. Am J Hypertens. 1991; 4, 635641.CrossRefGoogle ScholarPubMed
Donate-Correa, J, Martin-Nunez, E, Muros-de-Fuentes, M, Mora-Fernandez, C, Navarro-Gonzalez, JF. Inflammatory cytokines in diabetic nephropathy. J Diabetes Res. 2015; 2015, 948417.CrossRefGoogle ScholarPubMed
Ho, AW, Wong, CK, Lam, CW. Tumor necrosis factor-alpha up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways. Immunobiology. 2008; 213, 533544.CrossRefGoogle ScholarPubMed
Frank, PG, Lisanti, MP. ICAM-1: role in inflammation and in the regulation of vascular permeability. Am J Physiol Heart Circ Physiol. 2008; 295, H926H927.CrossRefGoogle ScholarPubMed
Rudemiller, NP, Crowley, SD. The role of chemokines in hypertension and consequent target organ damage. Pharmacol Res. 2017; 119, 404411.CrossRefGoogle ScholarPubMed
Kashyap, S, Warner, GM, Hartono, SP, et al. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension. Am J Physiol Renal Physiol. 2016; 310, F372F384. ScholarPubMed
Ishibashi, M, Hiasa, K, Zhao, Q, et al. Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling. Circ Res. 2004; 94, 12031210. ScholarPubMed
Usui, M, Egashira, K, Tomita, H, et al. Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats. Circulation. 2000; 101, 305310.CrossRefGoogle ScholarPubMed
Miravete, M, Dissard, R, Klein, J, et al. Renal tubular fluid shear stress facilitates monocyte activation toward inflammatory macrophages. Am J Physiol Renal Physiol. 2012; 302, F1409F1417.CrossRefGoogle ScholarPubMed
Hilgers, KF, Hartner, A, Porst, M, et al. Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury. Kidney Int. 2000; 58, 24082419.CrossRefGoogle ScholarPubMed
Taal, MW, Zandi-Nejad, K, Weening, B, et al. Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney. Kidney Int. 2000; 58, 16641676.CrossRefGoogle ScholarPubMed
Blasi, ER, Rocha, R, Rudolph, AE, et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003; 63, 17911800.CrossRefGoogle ScholarPubMed
Perry, MA, Granger, DN. Role of CD11/CD18 in shear rate-dependent leukocyte-endothelial cell interactions in cat mesenteric venules. J Clin Invest. 1991; 87, 17981804.CrossRefGoogle ScholarPubMed
Barreiro, O, Martin, P, Gonzalez-Amaro, R, Sanchez-Madrid, F. Molecular cues guiding inflammatory responses. Cardiovasc Res. 2010; 86, 174182.CrossRefGoogle ScholarPubMed
Ojeda, NB, Grigore, D, Alexander, BT. Developmental programming of hypertension: insight from animal models of nutritional manipulation. Hypertension. 2008; 52, 4450.CrossRefGoogle ScholarPubMed
Langley-Evans, SC, Welham, SJ, Jackson, AA. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 1999; 64, 965974.CrossRefGoogle ScholarPubMed
Chen, CM, Chou, HC. Effects of maternal undernutrition on glomerular ultrastructure in rat offspring. Pediatr Neonatol. 2009; 50, 5053.CrossRefGoogle ScholarPubMed
Schreuder, MF, Nyengaard, JR, Remmers, F, van Wijk, JA, Delemarre-van de Waal, HA. Postnatal food restriction in the rat as a model for a low nephron endowment. Am J Physiol Renal Physiol. 2006; 291, F1104F1107.CrossRefGoogle ScholarPubMed
Serri, O, St-Jacques, P, Sartippour, M, Renier, G. Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy. J Clin Endocrinol Metab. 1999; 84, 5863.Google ScholarPubMed
Andreassen, M, Frystyk, J, Faber, J, Kristensen, LO. GH activity and markers of inflammation: a crossover study in healthy volunteers treated with GH and a GH receptor antagonist. Eur J Endocrinol. 2012; 166, 811819.CrossRefGoogle Scholar
Deepak, D, Daousi, C, Javadpour, M, et al. The influence of growth hormone replacement on peripheral inflammatory and cardiovascular risk markers in adults with severe growth hormone deficiency. Growth Horm IGF Res. 2010; 20, 220225.CrossRefGoogle ScholarPubMed
Chen, Y, Sood, S, Krishnamurthy, VM, Rotwein, P, Rabkin, R. Endotoxin-induced growth hormone resistance in skeletal muscle. Endocrinology. 2009; 150, 36203626.CrossRefGoogle ScholarPubMed
Aurensanz Clemente, E, Ayerza Casas, A, Samper Villagrasa, P, Ruiz Frontera, P, Bueno Lozano, G. Evaluation of cardiac function in a group of small for gestational age school-age children treated with growth hormone. Med Clin. 2017; 148, 101106.CrossRefGoogle Scholar
Sas, T, Mulder, P, Hokken-Koelega, A. Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency. J Clin Endocrinol Metab. 2000; 85, 37863792.Google ScholarPubMed
Pawlikowska-Haddal, A. Growth hormone therapy with norditropin (somatropin) in growth hormone deficiency. Expert Opin Biol Ther. 2013; 13, 927932.CrossRefGoogle Scholar
Stochholm, K, Johannsson, G. Reviewing the safety of GH replacement therapy in adults. Growth Horm IGF Res. 2015; 25, 149157.CrossRefGoogle ScholarPubMed
Carroll, PV, Van den Berghe, G. Safety aspects of pharmacological GH therapy in adults. Growth Horm IGF Res. 2001; 11, 166172.CrossRefGoogle ScholarPubMed
Whitney, JL, Bilkan, CM, Sandberg, K, Myers, AK, Mulroney, SE. Growth hormone exacerbates diabetic renal damage in male but not female rats. Biol Sex Differ. 2013; 4, 12.CrossRefGoogle Scholar
Flyvbjerg, A, Bennett, WF, et al. Compensatory renal growth in uninephrectomized adult mice is growth hormone dependent. Kidney Int. 1999; 56, 20482054.CrossRefGoogle ScholarPubMed
Flyvbjerg, A. The role of growth hormone in the pathogenesis of diabetic kidney disease. Pediatr Endocrinol Rev. 2004; 1, 525529.Google ScholarPubMed
Bellush, LL, Doublier, S, Holland, AN, et al. Protection against diabetes-induced nephropathy in growth hormone receptor/binding protein gene-disrupted mice. Endocrinology. 2000; 141, 163168.CrossRefGoogle ScholarPubMed