Abstract
This study was performed to identify transcriptional alterations in male intrauterine growth restricted (IUGR) rats during and at the end of nephrogenesis in order to generate hypotheses which molecular mechanisms contribute to adverse kidney programming. IUGR was induced by low protein (LP) diet throughout pregnancy, bilateral uterine vessel ligation (LIG), or intrauterine stress (IUS) by sham operation. Offspring of unimpaired dams served as controls. Significant acute kidney damage was ruled out by negative results for proteins indicative of ER-stress, autophagy, apoptosis, or infiltration with macrophages. Renal gene expression was examined by transcriptome microarrays, demonstrating 53 (LP, n = 12; LIG, n = 32; IUS, n = 9) and 134 (LP, n = 10; LIG, n = 41; IUS, n = 83) differentially expressed transcripts on postnatal days (PND) 1 and 7, respectively. Reduced Pilra (all IUGR groups, PND 7), Nupr1 (LP and LIG, PND 7), and Kap (LIG, PND 1) as well as increased Ccl20, S100a8/a9 (LIG, PND 1), Ifna4, and Ltb4r2 (IUS, PND 7) indicated that inflammation-related molecular dysregulation could be a “common” feature after IUGR of different origins. Network analyses of transcripts and predicted upstream regulators hinted at proinflammatory adaptions mainly in LIG (arachidonic acid-binding, neutrophil aggregation, toll-like-receptor, NF-kappa B, and TNF signaling) and dysregulation of AMPK and PPAR signaling in LP pups. The latter may increase susceptibility towards obesity-associated kidney damage. Western blots of the most prominent predicted upstream regulators confirmed significant dysregulation of RICTOR in LP (PND 7) and LIG pups (PND 1), suggesting that mTOR-related processes could further modulate kidney programming in these groups of IUGR pups.Key messagesInflammation-related transcripts are dysregulated in neonatal IUGR rat kidneys.Upstream analyses indicate renal metabolic dysregulation after low protein diet.RICTOR is dysregulated after low protein diet and uterine vessel ligation.
Highlights
Adverse environmental conditions during intrauterine and early postnatal life have been linked to the predisposition for noncommunicable diseases in later life [1]
Direct comparison of kidneys during early postnatal life from intrauterine growth restriction (IUGR) offspring after (1) low protein (LP) diet throughout pregnancy [16, 19], (2) bilateral uterine vessel ligation (LIG) during terminal pregnancy [16, 17, 24,25,26], and (3) intrauterine stress (IUS) by sham operation in late pregnancy [16, 17, 24,25,26] with a control (C) group offers the unique opportunity to differentiate the molecular details of early kidney programming either after nutritional protein deficiency or reduced uterine blood flow or intrauterine stress
Birth weight was significantly reduced in all three groups of IUGR pups (Fig. 2a)
Summary
Adverse environmental conditions during intrauterine and early postnatal life have been linked to the predisposition for noncommunicable diseases in later life [1]. Insufficient intrauterine nutrient supply induces intrauterine growth restriction (IUGR) and is a major cause of low birth weight [1, 2, 4, 5]. The developing kidney is susceptible to adverse environmental impacts since even small changes in gene or protein expression during critical time spans may lead to severely altered renal outcome [13]. Nephrogenesis continues until postnatal day (PND) 8 [15]. Rat kidney development in the first postnatal week of life corresponds to human renal development in the third trimester
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