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Altered molecular signatures during kidney development after intrauterine growth restriction of different origins.

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 MESSAGES: Inflammation-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.

SUBMITTER: Nusken E

PROVIDER: S-EPMC7080693 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Altered molecular signatures during kidney development after intrauterine growth restriction of different origins.

Nüsken Eva E Fink Gregor G Lechner Felix F Voggel Jenny J Wohlfarth Maria M Sprenger Lisa L Mehdiani Nava N Weber Lutz T LT Liebau Max Christoph MC Brachvogel Bent B Dötsch Jörg J Nüsken Kai-Dietrich KD

Journal of molecular medicine (Berlin, Germany) 20200201 3

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 ...[more]

PMID: 32008055

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Project description:Frequent occurrence of intrauterine growth restriction (IUGR) causes huge economic losses in the pig industry. Accelerated catch-up growth (CUG) in the early stage of life could restore multiple adverse outcomes of IUGR offspring; however, there is little knowledge about this beneficial phenomenon. We previously found that nutrient absorption related to intestinal function was globally promoted in CUG-IUGR piglets before weaning, which might be the dominant reason for CUG, but what this alteration could lead to in subsequent liver metabolism is still unknown. Firstly, a Normal, CUG, and non-catch-up growth (NCUG) piglet model before weaning was established by dividing eighty litters of newborn piglets into normal birth weight (NBW) and IUGR groups according to birth weight, and those piglets with IUGR but above-average weanling body weight were considered CUG, and the piglets with IUGR still below average body weight were considered NCUG at weaning day (d 26). Liver samples were collected and then systematically compared in glycolipid metabolism, mitochondrial function, antioxidant status, and inflammatory status among these three different growth models. Enhanced hepatic uptake of fatty acids, diminished de novo synthesis of fatty acids, and increased oxidation of fatty acids were observed in CUG livers compared to Normal and NCUG. In contrast, the NCUG liver showed enhanced glucose uptake and gluconeogenesis compared to Normal and CUG. We also observed deteriorating hepatic vacuolation in NCUG piglets, while increasing hepatic lipid deposition in CUG piglets. Besides, the expression of genes related to mitochondrial energy metabolism and biogenesis was reduced in CUG piglets and the phosphorylation level of AMPK was significantly higher compared to Normal (p < 0.05). Moreover, NCUG liver showed decreased T-AOC (p < 0.01) and GSH-PX (p < 0.05), increased MDA concentrations (p < 0.01), upregulated phosphorylation levels of ERK and NF-κB (p < 0.05), and elevated pro-inflammatory factors IL-1β, IL-6 and TNF-α (p < 0.05) compared to Normal. Furthermore, correlation analysis revealed a significant positive correlation between glucose metabolism and inflammatory factors, while a negative correlation between mitochondrial function-related genes and fatty acid transport. NGUG piglets showed simultaneous enhancement of glucose uptake and gluconeogenesis, as well as reduced antioxidant capacity and increased inflammatory status, whereas CUG comes at the expense of impaired hepatic mitochondrial function and pathological fat accumulation.

Project description:Intrauterine growth restriction (IUGR) is a leading cause of neonatal morbidity and mortality in humans and domestic animals. Developmental adaptations of skeletal muscle in IUGR lead to increased risk of premature muscle loss and metabolic disease in later life. Here, we identified β-Klotho (KLB), a fibroblast growth factor 21 (FGF21) co-receptor, as a novel regulator of muscle development in IUGR. Using the pig as a naturally-occurring disease model, we performed transcriptome-wide profiling of fetal muscle (day 90 of pregnancy) from IUGR and normal-weight (NW) littermates. We found that, alongside large-scale transcriptional changes comprising multiple developmental, tissue injury and metabolic gene pathways, KLB was increased in IUGR muscle. Moreover, FGF21 concentrations were increased in plasma in IUGR fetuses. Using cultures of fetal muscle progenitor cells (MPCs), we showed reduced myogenic capacity of IUGR compared to NW muscle in vitro, as evidenced by differences in fusion indices and myogenic transcript levels, as well as mechanistic target of rapamycin (mTOR) activity. Moreover, transfection of MPCs with KLB small interfering RNA promoted myogenesis and mTOR activation, whereas treatment with FGF21 had opposite and dose-dependent effects in porcine and also in human fetal MPCs. In conclusion, our results identify KLB as a novel and potentially critical mediator of impaired muscle development in IUGR, through conserved mechanisms in pigs and humans. Our data shed new light onto the pathogenesis of IUGR, a significant cause of lifelong ill-health in humans and animals. KEY POINTS: Intrauterine growth restriction (IUGR) is associated with large-scale transcriptional changes in developmental, tissue injury and metabolic gene pathways in fetal skeletal muscle. Levels of the fibroblast growth factor 21 (FGF21) co-receptor, β-Klotho (KLB) are increased in IUGR fetal muscle, and FGF21 concentrations are increased in IUGR fetal plasma. KLB mediates a reduction in muscle development through inhibition of mechanistic target of rapamycin signalling. These effects of KLB on muscle cells are conserved in pig and human, suggesting a vital role of this protein in the regulation of muscle development and function in mammals.

Project description:Consistency in clinical outcomes is key to the success of therapeutic Mesenchymal Stem/Stromal cells (MSCs) in regenerative medicine. MSCs are used to treat both humans and companion animals (horses, dogs, and cats). The properties of MSC preparations can vary significantly with factors including tissue of origin, donor age or health status. We studied the effects of developmental programming associated with intrauterine growth restriction (IUGR) on MSC properties, particularly related to multipotency. IUGR results from inadequate uterine capacity and placental insufficiency of multifactorial origin. Both companion animals (horses, dogs, cats) and livestock (pigs, sheep, cattle) can be affected by IUGR resulting in decreased body size and other associated changes that can include, alterations in musculoskeletal development and composition, and increased adiposity. Therefore, we hypothesized that this dysregulation occurs at the level of MSCs, with the cells from IUGR animals being more prone to differentiate into adipocytes and less to other lineages such as chondrocytes and osteocytes compared to those obtained from normal animals. IUGR has consequences on health and performance in adult life and in the case of farm animals, on meat quality. In humans, IUGR is linked to increased risk of metabolic (type 2 diabetes) and other diseases (cardiovascular), later in life. Here, we studied porcine MSCs where IUGR occurs spontaneously, and shows features that recapitulate human IUGR. We compared the properties of adipose-derived MSCs from IUGR (IUGR-MSCs) and Normal (Normal-MSCs) new-born pig littermates. Both MSC types grew clonally and expressed typical MSC markers (CD105, CD90, CD44) at similar levels. Importantly, tri-lineage differentiation capacity was significantly altered by IUGR. IUGR-MSCs had higher adipogenic capacity than Normal-MSCs as evidenced by higher adipocyte content and expression of the adipogenic transcripts, PPARγ and FABP4 (P < 0.05). A similar trend was observed for fibrogenesis, where, upon differentiation, IUGR-MSCs expressed significantly higher levels of COL1A1 (P < 0.03) than Normal-MSCs. In contrast, chondrogenic and osteogenic potential were decreased in IUGR-MSCs as shown by a smaller chondrocyte pellet and osteocyte staining, and lower expression of SOX9 (P < 0.05) and RUNX2 (P < 0.02), respectively. In conclusion, the regenerative potential of MSCs appears to be determined prenatally in IUGR and this should be taken into account when selecting cell donors in regenerative therapy programmes both in humans and companion animals.

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Altered molecular signatures during kidney development after intrauterine growth restriction of different origins.

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Altered molecular signatures during kidney development after intrauterine growth restriction of different origins.

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