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1.
Cells ; 13(6)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38534344

RESUMO

Intrauterine growth restriction (IUGR) and being small for gestational age (SGA) are two distinct conditions with different implications for short- and long-term child development. SGA is present if the estimated fetal or birth weight is below the tenth percentile. IUGR can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnion, lack of growth in the interval, estimated weight below the third percentile) and can also be present in fetuses and neonates with weights above the tenth percentile. There is a need to differentiate between IUGR and SGA whenever possible, as IUGR in particular is associated with greater perinatal morbidity, prematurity and mortality, as well as an increased risk for diseases in later life. Recognizing fetuses and newborns being "at risk" in order to monitor them accordingly and deliver them in good time, as well as to provide adequate follow up care to ameliorate adverse sequelae is still challenging. This review article discusses approaches to differentiate IUGR from SGA and further increase diagnostic accuracy. Since adverse prenatal influences increase but individually optimized further child development decreases the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood. Moreover, we present current concepts of pathophysiology, with a focus on oxidative stress and consecutive inflammatory and metabolic changes as key molecular mechanisms of adverse sequelae, and look at future scientific opportunities and challenges. Most importantly, awareness needs to be raised that pre- and postnatal care of IUGR neonates should be regarded as a continuum.


Assuntos
Retardo do Crescimento Fetal , Doenças do Recém-Nascido , Feminino , Humanos , Recém-Nascido , Gravidez , Feto , Recém-Nascido Prematuro , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Estresse Oxidativo
3.
Sci Rep ; 13(1): 4281, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36922538

RESUMO

Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF's active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p < 0.05) affected expression of 351 genes in podocytes. Gene Ontology term enrichment analysis particularly clustered terms related to actin and inflammation-related cell death. Indeed, quantification of the actin cytoskeleton of BSA treated podocytes revealed a significant increase of thickness and number of actin filaments after treatment with MPA. Further, MPA significantly reduced TNFα and cycloheximide induced cell death. MPA has a substantial effect on the transcriptome of podocytes in vitro, particularly including functional clusters related to non-immune cell dependent mechanisms. This may provide a molecular basis for direct beneficial effects of MPA on the structural integrity and survival of podocytes under pro-inflammatory conditions.


Assuntos
Ácido Micofenólico , Podócitos , Animais , Camundongos , Citoesqueleto de Actina/metabolismo , Sobrevivência Celular , Cicloeximida , Ácido Micofenólico/farmacologia , Podócitos/metabolismo
4.
Int J Mol Sci ; 24(3)2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36768831

RESUMO

Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.


Assuntos
Senilidade Prematura , Insuficiência Renal Crônica , Feminino , Camundongos , Animais , Gravidez , Humanos , Senilidade Prematura/metabolismo , Obesidade/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Envelhecimento/genética
5.
J Lipid Res ; 63(11): 100283, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36152882

RESUMO

Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female rats, we investigated 1) how an elevated dietary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular protein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intrauterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncompromised pregnancy. On postnatal (P) days P2-P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and proteomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus mitigating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proinflammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.


Assuntos
Ácidos Graxos Ômega-3 , Gravidez , Humanos , Animais , Ratos , Feminino , Ácidos Graxos Ômega-3/farmacologia , Dieta , Fosfolipídeos , Ácido Araquidônico , Retardo do Crescimento Fetal/metabolismo , Rim/metabolismo
6.
PLoS One ; 17(3): e0265988, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35344549

RESUMO

Maternal malnutrition is associated with decreased nutrient transfer to the foetus, which may lead to foetal growth restriction, predisposing children to a variety of diseases. However, regulation of placental nutrient transfer during decreased nutrient availability is not fully understood. In the present study, the aim was to investigate changes in levels of placental nutrient transporters accompanying maternal hypoglycaemia following different durations and stages of gestation in rats. Maternal hypoglycaemia was induced by insulin-infusion throughout gestation until gestation day (GD)20 or until end of organogenesis (GD17), with sacrifice on GD17 or GD20. Protein levels of placental glucose transporters GLUT1 (45/55 kDa isotypes) and GLUT3, amino acid transporters SNAT1 and SNAT2, and insulin receptor (InsR) were assessed. On GD17, GLUT1-45, GLUT3, and SNAT1 levels were increased and InsR levels decreased versus controls. On GD20, following hypoglycaemia throughout gestation, GLUT3 levels were increased, GLUT1-55 showed the same trend. After cessation of hypoglycaemia at end of organogenesis, GLUT1-55, GLUT3, and InsR levels were increased versus controls, whereas SNAT1 levels were decreased. The increases in levels of placental nutrient transporters seen during maternal hypoglycaemia and hyperinsulinemia likely reflect an adaptive response to optimise foetal nutrient supply and development during limited availability of glucose.


Assuntos
Hipoglicemia , Placenta , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Feminino , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Hipoglicemia/metabolismo , Troca Materno-Fetal , Nutrientes , Placenta/metabolismo , Gravidez , Ratos
7.
Nutrients ; 14(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35276811

RESUMO

Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by "sham" operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.


Assuntos
Retardo do Crescimento Fetal , Insuficiência Placentária , Animais , Feminino , Retardo do Crescimento Fetal/etiologia , Hipocampo/metabolismo , Masculino , Placenta/metabolismo , Gravidez , Ratos , Serina-Treonina Quinases TOR/metabolismo
8.
Semin Fetal Neonatal Med ; 27(1): 101245, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33994314

RESUMO

Adverse perinatal circumstances can cause acute kidney injury (AKI) and contribute to chronic kidney disease (CKD). Accumulating evidence indicate that a wide spectrum of perinatal conditions interferes with normal kidney development and ultimately leads to aberrant kidney structure and function later in life. The present review addresses the lack of mechanistic knowledge with regard to perinatal origins of CKD and provides a comprehensive overview of pre- and peri-natal insults, including genetic predisposition, suboptimal nutritional supply, obesity and maternal metabolic disorders as well as placental insufficiency leading to intrauterine growth restriction (IUGR), prematurity, infections, inflammatory processes, and the need for life-saving treatments (e.g. oxygen supplementation, mechanical ventilation, medications) in neonates. Finally, we discuss future preventive, therapeutic, and regenerative directions. In summary, this review highlights the perinatal vulnerability of the kidney and the early origins of increased susceptibility toward AKI and CKD during postnatal life. Promotion of kidney health and prevention of disease require the understanding of perinatal injury in order to optimize perinatal micro- and macro-environments and enable normal kidney development.


Assuntos
Injúria Renal Aguda , Doenças do Recém-Nascido , Doenças do Prematuro , Insuficiência Renal Crônica , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Feminino , Humanos , Recém-Nascido , Doenças do Prematuro/terapia , Rim , Placenta , Gravidez , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/prevenção & controle
9.
Nutr Metab (Lond) ; 18(1): 101, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34838065

RESUMO

Being born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p < 0.01) and restored in CLM fed animals (p < 0.05). LysoPC(18:2) levels at PN42 correlated inversely with adult blood glucose levels. These data indicate that early-life LysoPC(18:2) blood levels may predict adult blood glucose levels and are affected by a postnatal diet with an adapted lipid droplet structure in IUGR offspring.

10.
Am J Physiol Renal Physiol ; 321(1): F93-F105, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34056927

RESUMO

Intrauterine growth restriction (IUGR) due to an adverse intrauterine environment predisposes to arterial hypertension and loss of kidney function. Here, we investigated whether vascular dysregulation in renal interlobar arteries (RIAs) may contribute to hypertensive glomerular damage after IUGR. In rats, IUGR was induced by bilateral uterine vessel ligation. Offspring of nonoperated rats served as controls. From postnatal day 49, blood pressure was telemetrically recorded. On postnatal day 70, we evaluated contractile function in RIAs and mesenteric arteries. In addition, blood, urine, and glomerular parameters as well as renal collagen deposition were analyzed. IUGR RIAs not only showed loss of stretch activation in 9 of 11 arteries and reduced stretch-induced myogenic tone but also showed a shift of the concentration-response relation of acetylcholine-induced relaxation toward lower concentrations. However, IUGR RIAs also exhibited augmented contractions through phenylephrine. Systemic mean arterial pressure [mean difference: 4.8 mmHg (daytime) and 5.7 mmHg (night)], mean glomerular area (IUGR: 9,754 ± 338 µm2 and control: 8,395 ± 227 µm2), and urinary protein-to-creatinine ratio (IUGR: 1.67 ± 0.13 g/g and control: 1.26 ± 0.10 g/g) were elevated after IUGR. We conclude that male IUGR rat offspring may have increased vulnerability toward hypertensive glomerular damage due to loss of myogenic tone and augmented endothelium-dependent relaxation in RIAs.NEW & NOTEWORTHY For the first time, our study presents wire myography data from renal interlobar arteries (RIAs) and mesenteric arteries of young adult rat offspring after intrauterine growth restriction (IUGR). Our data indicate that myogenic tone in RIAs is dysfunctional after IUGR. Furthermore, IUGR offspring suffer from mild arterial hypertension, glomerular hypertrophy, and increased urinary protein-to-creatinine ratio. Dysregulation of vascular tone in RIAs could be an important variable that impacts upon vulnerability toward glomerular injury after IUGR.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Artéria Renal/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Retardo do Crescimento Fetal/fisiopatologia , Rim/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Fenilefrina/farmacologia , Ratos
12.
Mol Cell Pediatr ; 7(1): 17, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33269431

RESUMO

In the last years, great advances have been made in the effort to understand how nutritional influences can affect long-term renal health. Evidence has accumulated that maternal nutrition before and during pregnancy and lactation as well as early postnatal nutrition is of special significance. In this review, we summarize epidemiologic and experimental data on the renal effects of perinatal exposure to energy restriction, low-protein diet, high-fat diet, high-fructose diet, and high- and low-salt diet as well as micronutrient deficiencies. Interestingly, different modifications during early-life diet may end up with similar sequelae for the offspring. On the other hand, molecular pathways can be influenced in opposite directions by different dietary interventions during early life. Importantly, postnatal nutrition significantly modifies the phenotype induced by maternal diet. Sequelae of altered macro- or micronutrient intakes include altered nephron count, blood pressure dysregulation, altered sodium handling, endothelial dysfunction, inflammation, mitochondrial dysfunction, and oxidative stress. In addition, renal prostaglandin metabolism as well as renal AMPK, mTOR, and PPAR signaling can be affected and the renin-angiotensin-aldosterone system may be dysregulated. Lately, the influence of early-life diet on gut microbiota leading to altered short chain fatty acid profiles has been discussed in the etiology of arterial hypertension. Against this background, the preventive and therapeutic potential of perinatal nutritional interventions regarding kidney disease is an emerging field of research. Especially individuals at risk (e.g., newborns from mothers who suffered from malnutrition during gestation) could disproportionately benefit from well-targeted dietary interventions.

13.
J Mol Med (Berl) ; 98(3): 395-407, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32008055

RESUMO

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.


Assuntos
Retardo do Crescimento Fetal/genética , Rim/metabolismo , Animais , Animais Recém-Nascidos , Rim/crescimento & desenvolvimento , Masculino , Tamanho do Órgão , Ratos Wistar , Transcriptoma
14.
J Clin Med ; 8(5)2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31083566

RESUMO

There is accumulating evidence for fetal programming of later kidney disease by maternal obesity or associated conditions. We performed a hypothesis-generating study to identify potentially underlying mechanisms. Female mice were randomly split in two groups and fed either a standard diet (SD) or high fat diet (HFD) from weaning until mating and during pregnancy. Half of the dams from both groups were treated with metformin ((M), 380 mg/kg), resulting in four experimental groups (SD, SD-M, HFD, HFD-M). Caesarean section was performed on gestational day 18.5. Fetal kidney tissue was isolated from cryo-slices using laser microdissection methods and a proteomic screen was performed. For single proteins, a fold change ≥1.5 and q-value <0.05 were considered to be statistically significant. Interestingly, HFD versus SD had a larger effect on the proteome of fetal kidneys (56 proteins affected; interaction clusters shown for proteins concerning transcription/translation, mitochondrial processes, eicosanoid metabolism, H2S-synthesis and membrane remodeling) than metformin exposure in either SD (29 proteins affected; clusters shown for proteins involved in transcription/translation) or HFD (6 proteins affected; no cluster). By further analysis, ATP6V1G1, THY1, PRKCA and NDUFB3 were identified as the most promising candidates potentially mediating reprogramming effects of metformin in a maternal high fat diet.

15.
Front Pediatr ; 6: 36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535992

RESUMO

Chronic kidney disease affects more than 10% of the population. Programming studies have examined the interrelationship between environmental factors in early life and differences in morbidity and mortality between individuals. A number of important principles has been identified, namely permanent structural modifications of organs and cells, long-lasting adjustments of endocrine regulatory circuits, as well as altered gene transcription. Risk factors include intrauterine deficiencies by disturbed placental function or maternal malnutrition, prematurity, intrauterine and postnatal stress, intrauterine and postnatal overnutrition, as well as dietary dysbalances in postnatal life. This mini-review discusses critical developmental periods and long-term sequelae of renal programming in humans and presents studies examining the underlying mechanisms as well as interventional approaches to "re-program" renal susceptibility toward disease. Clinical manifestations of programmed kidney disease include arterial hypertension, proteinuria, aggravation of inflammatory glomerular disease, and loss of kidney function. Nephron number, regulation of the renin-angiotensin-aldosterone system, renal sodium transport, vasomotor and endothelial function, myogenic response, and tubuloglomerular feedback have been identified as being vulnerable to environmental factors. Oxidative stress levels, metabolic pathways, including insulin, leptin, steroids, and arachidonic acid, DNA methylation, and histone configuration may be significantly altered by adverse environmental conditions. Studies on re-programming interventions focused on dietary or anti-oxidative approaches so far. Further studies that broaden our understanding of renal programming mechanisms are needed to ultimately develop preventive strategies. Targeted re-programming interventions in animal models focusing on known mechanisms will contribute to new concepts which finally will have to be translated to human application. Early nutritional concepts with specific modifications in macro- or micronutrients are among the most promising approaches to improve future renal health.

16.
Pediatr Nephrol ; 33(4): 619-629, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29177628

RESUMO

BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood and traditionally considered as a self-limiting disease. However, renal involvement can unfavorably determine long-term prognosis. The reported regimens to treat HSP nephritis (HSPN) are diverse, indicating that the most effective treatment remains controversial. METHODS: This retrospective, single-center study involved 18 patients presenting with HSPN and nephrotic-range proteinuria. We aimed to investigate the efficacy and safety of mycophenolate mofetil (MMF) and identify a cut-off level for estimated mycophenolic acid area under the curve (eMPA-AUC0-12h) values, which can predict complete remission with high sensitivity. RESULTS: Despite prior insufficient therapeutic response to corticosteroids, 89% of patients showed a significant decrease in proteinuria after 1 month of MMF treatment. None of them relapsed during treatment; however, two children relapsed after discontinuation. Based on results of a receiver operating characteristic (ROC) analysis, an eMPA-AUC0-12h >56.4 mg*h/l was a predictor for complete remission within 3 months (80% sensitivity, 83.3% specificity, p = 0.035). During MMF administration, we encountered no adverse event requiring discontinuation of treatment. CONCLUSION: Our study demonstrates that MMF is a safe and potentially effective secondary treatment option for children with HSPN to achieve and maintain long-term remission without serious side effects. To achieve complete remission within 3 months, resolve severe inflammatory glomerular lesions, and avoid progression to chronic kidney disease, we propose timely diagnosis and early initiation of MMF with an eMPA-AUC0-12h value of 56.4 mg*h/l.


Assuntos
Monitoramento de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Glucocorticoides/administração & dosagem , Vasculite por IgA/tratamento farmacológico , Ácido Micofenólico/administração & dosagem , Nefrite/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Alemanha , Glucocorticoides/efeitos adversos , Humanos , Vasculite por IgA/complicações , Rim/patologia , Masculino , Ácido Micofenólico/efeitos adversos , Nefrite/etiologia , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento
17.
J Reprod Immunol ; 122: 10-13, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28719804

RESUMO

Inflammation and oxidative stress are known to increase before labour. Whether gonadal white adipose tissue (gWAT) participates in this process and whether labour-related processes in placental and adipose tissue are altered in obese women is unknown. In our mouse model, lean mice display elevated placental inflammation and oxidative stress towards the end of pregnancy, accompanied by an increased expression of pro-inflammatory factors in gWAT. Obese mice also display elevated levels of pro-inflammatory factors and oxidative stress in placentas shortly before birth. However, placental infiltration with leukocytes and an increase in gWAT pro-inflammatory factor expression in obese dams are lacking.


Assuntos
Inflamação/imunologia , Obesidade/imunologia , Placenta/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Células Cultivadas , Dieta , Modelos Animais de Doenças , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Gravidez
18.
Endocrinology ; 157(5): 1813-25, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27007072

RESUMO

Leptin availability in perinatal life critically affects metabolic programming. We tested the hypothesis that uteroplacental insufficiency and intrauterine stress affect perinatal leptin availability in rat offspring. Pregnant rats underwent bilateral uterine vessel ligation (LIG; n = 14), sham operation (SOP; n = 12), or no operation (controls, n = 14). Fetal livers (n = 180), placentas (n = 180), and maternal blood were obtained 4 hours (gestational day [E] 19), 24 hours (E20), and 72 hours (E22) after surgery. In the offspring, we took blood samples on E22 (n = 44), postnatal day (P) 1 (n = 29), P2 (n = 16), P7 (n = 30), and P12 (n = 30). Circulating leptin (ELISA) was significantly reduced in LIG (E22, P1, P2) and SOP offspring (E22). Postnatal leptin surge was delayed in LIG but was accelerated in SOP offspring. Placental leptin gene expression (quantitative RT-PCR) was reduced in LIG (E19, E20, E22) and SOP (E20, E22). Hepatic leptin receptor (Lepr-a, mediating leptin degradation) gene expression was increased in LIG fetuses (E20, E22) only. Surprisingly, hypoxia-inducible factors (Hif; Western blot) were unaltered in placentas and were reduced in the livers of LIG (Hif1a, E20; Hif2a, E19, E22) and SOP (Hif2a, E19) fetuses. Gene expression of prolyl hydroxylase 3, a factor expressed under hypoxic conditions contributing to Hif degradation, was increased in livers of LIG (E19, E20, E22) and SOP (E19) fetuses and in placentas of LIG and SOP (E19). In summary, reduced placental leptin production, increased fetal leptin degradation, and persistent perinatal hypoleptinemia are present in intrauterine growth restriction offspring, especially after uteroplacental insufficiency, and may contribute to perinatal programming of leptin resistance and adiposity in later life.


Assuntos
Leptina/metabolismo , Placenta/metabolismo , Insuficiência Placentária/metabolismo , Receptores para Leptina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leptina/sangue , Leptina/genética , Fígado/metabolismo , Insuficiência Placentária/sangue , Insuficiência Placentária/genética , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores para Leptina/genética
19.
J Cell Biochem ; 117(7): 1594-603, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26590355

RESUMO

Regulation of placental nutrient transport significantly affects fetal development and may modify intrauterine growth restriction (IUGR) and fetal programming. We hypothesized that placental nutrient transporters are differentially affected both by utero-placental insufficiency and prenatal surgical stress. Pregnant rats underwent bilateral uterine artery and vein ligation (LIG), sham operation (SOP) or no operation (controls, C) on gestational day E19. Placentas were obtained by caesarean section 4 h (LIG, n=20 placentas; SOP, n=24; C, n=12), 24 h (LIG, n=28; SOP, n=20; C, n=12) and 72 h (LIG, n=20; SOP, n=20; C, n=24) after surgery. Gene and protein expression of placental nutrient transporters for fatty acids (h-FABP, CD36), amino acids (SNAT1, SNAT2) and glucose (GLUT-1, Connexin 26) were examined by qRT-PCR, western blot and immunohistochemistry. Interestingly, the mean protein expression of h-FABP was doubled in placentas of LIG and SOP animals 4, 24 (SOP significant) and 72 h (SOP significant) after surgery. CD36 protein was significantly increased in LIG after 72 h. SNAT1 and SNAT2 protein and gene expressions were significantly reduced in LIG and SOP after 24 h. Further significantly reduced proteins were GLUT-1 in LIG (4 h, 72 h) and SOP (24 h), and Connexin 26 in LIG (72 h). In conclusion, placental nutrient transporters are differentially affected both by reduced blood flow and stress, probably modifying the already disturbed intrauterine milieu and contributing to IUGR and fetal programming. Increased fatty acid transport capacity may affect energy metabolism and could be a compensatory reaction with positive effects on brain development. J. Cell. Biochem. 117: 1594-1603, 2016. © 2015 Wiley Periodicals, Inc.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Antígenos CD36/metabolismo , Conexinas/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Placenta/metabolismo , Animais , Conexina 26 , Proteína 3 Ligante de Ácido Graxo , Feminino , Gravidez , Ratos , Ratos Wistar
20.
Pediatr Nephrol ; 30(7): 1173-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25787071

RESUMO

BACKGROUND: Growth restriction and retarded bone age are common findings in children with chronic kidney disease (CKD). We compared the automated BoneXpert™ method with the manual assessment of an X-ray of the non-dominant hand. METHODS: In this retrospective multicenter study, 359 patients with CKD stages 2-5, aged 2-14.5 (girls) or 2.5-17 years (boys) were included. Bone age was determined manually by three experts (according to Greulich and Pyle). Automated determination of bone age was performed using the image analysis software BoneXpert™. RESULTS: There was a strong correlation between the automatic and the manual method (r = 0.983, p < 0.001). The automatic method tended to generate higher bone age values (0.64 ± 0.73 years) in the younger patients (4-5 years) and to underestimate retardation or acceleration of bone age. The so-called "bone health index" (BHI) was reduced in comparison to the reference population. Bone health index standard deviation score (BHI-SDS) was not related to the stage of CKD, but weakly negatively correlated with plasma PTH concentrations (r = 0.12, p = 0.019). CONCLUSIONS: BoneXpert™ allows an objective, time-saving, and in general valid bone age assessment in children with CKD. Possible underestimation of retarded or accelerated bone age should be taken into account. Validation of the BHI needs further study.


Assuntos
Determinação da Idade pelo Esqueleto/métodos , Doenças Ósseas/diagnóstico , Doenças Ósseas/etiologia , Insuficiência Renal Crônica/complicações , Adolescente , Automação , Doenças Ósseas/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/patologia , Mãos/diagnóstico por imagem , Nível de Saúde , Humanos , Processamento de Imagem Assistida por Computador , Testes de Função Renal , Masculino , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos Retrospectivos
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