Uteroplacental insufficiency affects kidney VEGF expression in a model of IUGR with compensatory glomerular hypertrophy and hypertension

Abstract

Low nephron endowment secondary to intrauterine growth restriction (IUGR) results in compensatory hypertrophy of the remaining glomeruli, which in turn is associated with hypertension. However, gender differences exist in the response of the kidney to injury, and IUGR female offspring seems protected from an unfavorable outcome. We previously reported differences in gender-specific gene expression in the IUGR kidney as well as increased circulating corticosterone levels following uteroplacental insufficiency (UPI). Vascular endothelial growth factor (VEGF), which is critical for renal development, is an important candidate in the IUGR kidney since its expression can be regulated by sex-steroids and glucocorticoids. We hypothesize that IUGR leads to altered kidney VEGF expression in a gender-specific manner. Following uterine ligation in the pregnant rat, UPI decreases renal VEGF levels in male and female IUGR animals at birth and through postnatal day 21. However, by day 120 of life, IUGR females have increased kidney VEGF expression, not present in the IUGR males. In addition, IUGR males exhibit increased serum testosterone levels as well as proteinuria. These findings are intriguing in light of the difference in glomerular hypertrophy observed: IUGR males show increased glomerular area when compared to IUGR females. In this model characterized by decreased nephron number and adult onset hypertension, UPI decreases renal VEGF expression during nephrogenesis. Our most intriguing finding is the increased renal VEGF levels in adult IUGR females, associated with a more benign phenotype. We suggest that the mechanisms underlying renal disease in response to IUGR are most likely regulated in a gender specific manner.

Intrauterine Growth Restriction Decreases Endochondral Ossification and Bone Strength in Female Rats

“…This is not surprising as low body weight is common to the IUGR phenotype. 15,[19][20][21] As previously noted, postnatal growth is controlled through GHregulated systemic and tissue release of IGF-1. In mice, deletion of the IGF-1 gene leads to reduced birth size and severe postnatal growth restriction.…”

“…[19][20][21] All procedures were approved by the University of Utah Animal Care Committee and are in accordance with the American Physiological Society's guiding principles. 22 The surgical procedures described in detail 20,21 are summarized here.…”

Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth‐restricted rats

“…The phenotypic consequences of bilateral intrauterine artery ligation to the F1 generation rats are well established and include the MetS phenotype of insulin resistance, diabetes, hypertriglyceridemia, dyslipidemia, and hypertension (13,55,62,63). Additionally, a myriad of physiologic and biochemical changes underlying the phenotype have been found.…”

Chronic Kidney Disease: A Life Course Health Development Perspective

“…low nephron number with adult-onset hypertension, proteinuria, and glomerulosclerosis, especially in the setting of additional postnatal stressors such as high-protein diet or additional glomerular injury (Schreuder and Nauta 2007;Baserga et al 2009Baserga et al , 2010Merlet-Benichou et al 1994;Schreuder et al 2005;Shen et al 2011;Plank et al 2010). Alterations in expression of ureteric bud branching factors including downregulation of Pax2, GDNF, FGF7, BMP4, WNT4, and WNT11 mRNAs have been identified and may contribute to the decrease in nephron number (Abdel-Hakeem et al 2008;Buffat et al 2007).…”