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Porcari CY, Lencina CA, Amigone JL, Antunes-Rodrigues J, Caeiro XE, Godino A. Impact of perinatal hypertonic NaCl access on adult offspring's sodium intake and angiotensin and vasopressin systems under hypertension model. Sci Rep 2025; 15:8933. [PMID: 40089597 PMCID: PMC11910541 DOI: 10.1038/s41598-025-93238-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/05/2025] [Indexed: 03/17/2025] Open
Abstract
Perinatal natriophilia has programming effects on blood pressure control, inducing anatomical and molecular changes in the kidney and brain that impair blood pressure reestablishment after a pressor challenge, such as an osmotic stimulation. However, the imprinted effect of voluntary sodium consumption during this period on the development of hypertension is unclear. To evaluate this, we studied the effect of deoxycorticosterone acetate and high-salt diet (DOCA-salt) treatment on blood pressure and sodium intake responses, and gene expression in the kidney and brain in adult offspring exposed to voluntary hypertonic sodium consumption during the perinatal period (PM-NaCl group). Male PM-NaCl rats consumed more sodium than controls (PM-Ctrol group) during DOCA treatment. However, the hypertension induced did not differ between the PM-NaCl and PM-Ctrol groups. This behavioral change was accompanied by a higher angiotensin type 1 receptor (Agtr1a) gene expression at brain level in the subfornical organ and the hypothalamic paraventricular nucleus of PM-NaCl, areas key to the modulation of salt appetite and autonomic function. At renal level, programmed animals showed differing responses in gene expression induced by DOCA-salt treatment compared to the PM-Ctrol group, such as expression of Agtr1a, transient receptor potential vanilloid type 1 channel in the medulla and vasopressin 2 receptor in the renal cortex. The data indicates that the availability of a rich source of sodium during the perinatal period induces a long-term effect in DOCA-salt treated rats, modifying behavioral, brain and renal responses, suggesting that this early sodium exposure affects the vulnerability of the organisms to chronic non-communicable diseases mainly caused by changes in sodium intake and the regulatory mechanisms of the angiotensin and vasopressin systems.
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Affiliation(s)
- Cintia Y Porcari
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Friuli 2434, Córdoba, 5016, Argentina
| | - Cristina A Lencina
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Friuli 2434, Córdoba, 5016, Argentina
| | - José L Amigone
- Sección de Bioquímica Clínica, Hospital Privado, Córdoba, Argentina
| | - José Antunes-Rodrigues
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes 3900, Ribeirão Preto, CEP:14049-900, Brazil
| | - Ximena E Caeiro
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Friuli 2434, Córdoba, 5016, Argentina
| | - Andrea Godino
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Friuli 2434, Córdoba, 5016, Argentina.
- Facultad de Psicología, Universidad Nacional de Córdoba, Boulevard de la Reforma & Enf. Gordillo Gómez, Córdoba, 5000, Argentina.
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Ferreira ARO, Ribeiro MVG, Peres MNC, Lopes GKG, Saavedra LPJ, Piovan S, Barbosa LF, Raposo SR, Almeida DL, Malta A, Teixeira JJV, Mathias PCDF, Palma-Rigo K. Hypertension induced by peri-pubertal protein restriction depends on renin-angiotensin system dysfunction in adult male rats. Nutr Metab Cardiovasc Dis 2025; 35:103733. [PMID: 39448316 DOI: 10.1016/j.numecd.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 08/18/2024] [Accepted: 09/04/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND AND AIMS Hypertension depends on renin-angiotensin system dysfunction; however, little is known about its implications in the outcomes of neurogenic hypertension induced by peri-pubertal insults. This study aimed to evaluate whether hypertension induced by a peri-pubertal low-protein diet is related to renin-angiotensin system dysfunction in adult male Wistar rats. METHODS AND RESULTS Thirty-day-old male Wistar rats were fed a low-protein diet (4 % casein) for 30 days and subsequently fed a 20.5 % normal protein diet for a 60-day dietary recovery (LP group). Control animals (NP group) were fed a 20.5 % protein diet throughout their lives. Cardiovascular and renin-angiotensin system functions were evaluated on postnatal day 120 (6-24 animals per group). Statistical analyses were performed using the Student's t-test. Animals with LP show increased arterial blood pressure. The angiotensin 2 dose-response curve of LP animals showed an increase in the pressor response at a lower dose (50 ng/kg) and a reduction in the pressor response at a higher dose (400 ng/kg) compared with NP animals. Angiotensin 2 type 1 receptor mRNA levels were increased in the hearts of LP animals; however, angiotensin 2 type 2 receptor and MAS receptor mRNA levels were reduced. In the aorta, AT1 and AT2 mRNA levels were increased in LP animals, whereas MAS receptor mRNA levels were decreased in comparison to NP animals. CONCLUSION The renin-angiotensin system is disrupted in hypertension induced by protein restriction exposure during peri-pubertal life.
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MESH Headings
- Animals
- Male
- Renin-Angiotensin System
- Rats, Wistar
- Hypertension/physiopathology
- Hypertension/metabolism
- Hypertension/etiology
- Diet, Protein-Restricted
- Receptor, Angiotensin, Type 2/metabolism
- Receptor, Angiotensin, Type 2/genetics
- Disease Models, Animal
- Arterial Pressure/drug effects
- Age Factors
- Proto-Oncogene Mas
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins/genetics
- Angiotensin II
- Sexual Maturation
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 1/genetics
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Affiliation(s)
- Anna Rebeka Oliveira Ferreira
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Maiara Vanusa Guedes Ribeiro
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Maria Natalia Chimirri Peres
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Gabriel Kian Guimarães Lopes
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Lucas Paulo Jacinto Saavedra
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Silvano Piovan
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Leticia Ferreira Barbosa
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Scarllet Rodrigues Raposo
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Douglas Lopes Almeida
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Ananda Malta
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | | | - Paulo Cezar de Freitas Mathias
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil
| | - Kesia Palma-Rigo
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringa, Parana, Brazil; Adventist College of Parana, Ivatuba, Parana, Brazil.
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3
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Tain YL, Hsu CN. Kidney Programming and Hypertension: Linking Prenatal Development to Adulthood. Int J Mol Sci 2024; 25:13610. [PMID: 39769369 PMCID: PMC11677590 DOI: 10.3390/ijms252413610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/12/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
The complex relationship between kidney disease and hypertension represents a critical area of research, yet less attention has been devoted to exploring how this connection develops early in life. Various environmental factors during pregnancy and lactation can significantly impact kidney development, potentially leading to kidney programming that results in alterations in both structure and function. This early programming can contribute to adverse long-term kidney outcomes, such as hypertension. In the context of kidney programming, the molecular pathways involved in hypertension are intricate and include epigenetic modifications, oxidative stress, impaired nitric oxide pathway, inappropriate renin-angiotensin system (RAS) activation, disrupted nutrient sensing, gut microbiota dysbiosis, and altered sodium transport. This review examines each of these mechanisms and highlights reprogramming interventions proposed in preclinical studies to prevent hypertension related to kidney programming. Given that reprogramming strategies differ considerably from conventional treatments for hypertension in kidney disease, it is essential to shift focus toward understanding the processes of kidney programming and its role in the development of programmed hypertension.
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Affiliation(s)
- You-Lin Tain
- Division of Pediatric Nephrology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Rabadi MM, Verde MR, Camilliere M, Vecchio N, Kandhi S, Sekulic M, Wolin MS, Ratliff BB. Renal and Vascular Functional Decline in Aged Low Birth Weight Murine Adults. Kidney Blood Press Res 2024; 49:1075-1090. [PMID: 39571568 DOI: 10.1159/000542141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/16/2024] [Indexed: 12/19/2024] Open
Abstract
INTRODUCTION Maternal undernutrition (MUN)-induced low birth weight (LBW) neonates are susceptible to the development of high blood pressure and kidney disease later in life, although the underlying pathological causes remain unclear. The study here investigated the role of renal oxidative stress, impairment of vascular function, and altered sensitivity to angiotensin II (Ang II) as factors that contribute to these pathologies in aged LBW mice. METHODS LBW offspring were generated using a combined protein and caloric restricted MUN mouse model. The resulting LBW offspring were examined 1 year after birth for mean arterial blood pressure (MABP) (carotid artery catheterization), renal blood flow (RBF) (laser Doppler flowmetry), glomerular filtration rate (GFR) (sinistrin clearance), vasoreactivity (myograph), renal vascular density (CD31 staining), and reactive oxygen species (ROS) (ROS probes). Immunoblotting examined Ang II type 1 receptor (AT1R), soluble guanylate cyclase (sGC), and antioxidant systems. Pharmacological agents delivered to animals included the sGC stimulator δ-aminolevulinic acid (ALA), the AT1R inhibitor losartan, the antioxidant ethyl pyruvate (EP), and the toll-like receptor 4 inhibitor TAK242. RESULTS After 1 year, MABP was increased, while RBF, GFR, vascular reactivity, renal vascular density, and sGC were all reduced in the LBW aged adult. All four pharmacological agents improved MABP, RBF, GFR, vascular density, and vascular reactivity. Renal ROS was increased in the LBW adult but was reduced by ALA, EP, and TAK242 treatment. AT1R was upregulated in the LBW adult, while sGC was decreased, an effect reversed by ALA treatment. Endogenous antioxidant systems, including SOD1, catalase, and glutathione were downregulated in the LBW adult. CONCLUSION MUN-induced LBW mice experience increased Ang II sensitivity and oxidative stress. The increased Ang II sensitivity and ROS generation influences vascular density and reactivity, which drive an increase in MABP, and a concomitantly decrease in RBF and glomerular filtration. Pharmacological intervention that inhibits AT1R, enhances levels of sGC, reduces ROS, or inhibits toll-like receptor 4 improves vascular and renal function in the LBW adult.
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Affiliation(s)
- May M Rabadi
- Department of Medicine, New York Medical College, Valhalla, New York, USA
| | - Marella R Verde
- Department of Physiology, New York Medical College, Valhalla, New York, USA
| | - Mia Camilliere
- Department of Pathology, New York Medical College, Valhalla, New York, USA
| | - Nicholas Vecchio
- Department of Medicine, New York Medical College, Valhalla, New York, USA
| | - Sharath Kandhi
- Department of Physiology, New York Medical College, Valhalla, New York, USA
| | - Miroslav Sekulic
- Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, New York, USA
| | - Michael S Wolin
- Department of Physiology, New York Medical College, Valhalla, New York, USA
| | - Brian B Ratliff
- Department of Medicine, New York Medical College, Valhalla, New York, USA
- Department of Physiology, New York Medical College, Valhalla, New York, USA
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Campbell N, Deer E, Solise D, Cornelius DC, Turner T, Amaral LM, Herrock O, Jordan A, Shukla S, Ibrahim T, LaMarca B. AT1-AA Is Produced in Offspring in Response to Placental Ischemia and Is Lowered by B-Cell Depletion Without Compromising Overall Offspring Health. J Am Heart Assoc 2024; 13:e031417. [PMID: 38353227 PMCID: PMC11010106 DOI: 10.1161/jaha.123.031417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 12/01/2023] [Indexed: 02/21/2024]
Abstract
BACKGROUND Preeclampsia, new-onset hypertension during pregnancy alongside other organ dysfunction, is the leading cause of mortality for the mother and low birth weight for the baby. Low birth weight contributes to high risk of cardiovascular disorders later in life. Women with preeclampsia have activated B cells producing agonistic autoantibodies to AT1-AA (angiotensin II type I receptor). We hypothesize that rituximab, a B cell-depleting chemotherapeutic, will deplete maternal B cells in reduced uterine perfusion pressure (RUPP) rats without worsening the effect of placental ischemia on pup growth and survival. METHODS AND RESULTS To test this hypothesis, the RUPP procedure was performed, and rituximab was continuously infused via miniosmotic pump. Maternal blood and tissues were collected. A separate group of dams were allowed to deliver, pup weights were recorded, and at 4 months of age, tissues were collected from offspring. Immune cells were measured via flow cytometry, and AT1-AA was quantified using a contraction bioassay. Blood pressure increased in RUPP rats and was normalized with rituximab treatment. RUPP offspring also had increased circulating B cells, cytolytic natural killer cells, and increased circulating AT1-AA, which were normalized with maternal rituximab treatment. This is the first study to analyze the AT1-AA in RUPP offspring, which was normalized with rituximab. CONCLUSIONS Our findings indicate that perinatal rituximab lowers maternal mean arterial pressure in RUPP rats and improves birth weight, circulating AT1-AA, and circulating natural killer cells, indicating that rituximab improves adverse fetal outcomes in response to placental ischemia.
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Affiliation(s)
- Nathan Campbell
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Evangeline Deer
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Dylan Solise
- Department of Obstetrics and GynecologyUniversity of Mississippi Medical CenterJacksonMS
| | - Denise C. Cornelius
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
- Department of Emergency MedicineUniversity of Mississippi Medical CenterJacksonMS
| | - Ty Turner
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Lorena M. Amaral
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Owen Herrock
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Ariel Jordan
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Shivani Shukla
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Tarek Ibrahim
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
| | - Babbette LaMarca
- Department of Pharmacology & ToxicologyUniversity of Mississippi Medical CenterJacksonMS
- Department of Obstetrics and GynecologyUniversity of Mississippi Medical CenterJacksonMS
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Cardiovascular and renal profiles in rat offspring that do not undergo catch-up growth after exposure to maternal protein restriction. J Dev Orig Health Dis 2023; 14:426-436. [PMID: 36647740 DOI: 10.1017/s2040174422000666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Maternal protein restriction is often associated with structural and functional sequelae in offspring, particularly affecting growth and renal-cardiovascular function. However, there is little understanding as to whether hypertension and kidney disease occur because of a primary nephron deficit or whether controlling postnatal growth can result in normal renal-cardiovascular phenotypes. To investigate this, female Sprague-Dawley rats were fed either a low-protein (LP, 8.4% protein) or normal-protein (NP, 19.4% protein) diet prior to mating and until offspring were weaned at postnatal day (PN) 21. Offspring were then fed a non 'growth' (4.6% fat) which ensured that catch-up growth did not occur. Offspring growth was determined by weight and dual energy X-ray absorptiometry. Nephron number was determined at PN21 using the disector-fractionator method. Kidney function was measured at PN180 and PN360 using clearance methods. Blood pressure was measured at PN360 using radio-telemetry. Body weight was similar at PN1, but by PN21 LP offspring were 39% smaller than controls (Pdiet < 0.001). This difference was due to proportional changes in lean muscle, fat, and bone content. LP offspring remained smaller than NP offspring until PN360. In LP offspring, nephron number was 26% less in males and 17% less in females, than NP controls (Pdiet < 0.0004). Kidney function was similar across dietary groups and sexes at PN180 and PN360. Blood pressure was similar in LP and NP offspring at PN360. These findings suggest that remaining on a slow growth trajectory after exposure to a suboptimal intrauterine environment does not lead to the development of kidney dysfunction and hypertension.
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Alkhalefah A, Eyre HJ, Hussain R, Glazier JD, Ashton N. Impact of maternal intermittent fasting during pregnancy on cardiovascular, metabolic and renal function in adult rat offspring. PLoS One 2022; 17:e0258372. [PMID: 35271586 PMCID: PMC8912128 DOI: 10.1371/journal.pone.0258372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/08/2022] [Indexed: 11/18/2022] Open
Abstract
Pregnant Muslim women are exempt from fasting during Ramadan; however a majority are reported to fast. The impact of this form of maternal intermittent fasting (IF) on fetal development and offspring health is not well defined. Using a rat model, we have shown previously that maternal IF results in fetal growth restriction accompanied by changes in placental nutrient transport function. The aim of this study was to assess cardiovascular, metabolic and renal function in adult offspring of IF-exposed dams. Food was withheld from Wistar rats from 17:00 to 09:00 daily throughout pregnancy; controls had ad libitum access to food. Birth weight was unaffected; however male IF pups grew more slowly up to 10 weeks of age (P < 0.01) whereas IF females matched their control counterparts. Systolic blood pressure (SBP), glucose tolerance and basal renal function at 14 weeks were not affected by IF exposure. When offered saline solutions (0.9–2.1%) to drink, females showed a greater salt preference than males (P < 0.01); however there were no differences between dietary groups. A separate group of pups was weaned onto a 4% NaCl diet. SBP increased in IF pups sooner, at 7 weeks (P < 0.01), than controls which became hypertensive from 10 weeks. Renal function did not appear to differ; however markers of renal injury were elevated in IF males (P < 0.05). Maternal IF does not affect resting cardiovascular, metabolic and renal function; but when challenged by dietary salt load male IF offspring are more prone to renal injury.
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Affiliation(s)
- Alaa Alkhalefah
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
- Division of Developmental Biology and Medicine, Maternal and Fetal Health Research Centre, St. Mary’s Hospital, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Heather J. Eyre
- Divison of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Rezwana Hussain
- Division of Developmental Biology and Medicine, Maternal and Fetal Health Research Centre, St. Mary’s Hospital, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Jocelyn D. Glazier
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Nick Ashton
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
- * E-mail:
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Awazu M. Structural and functional changes in the kidney caused by adverse fetal and neonatal environments. Mol Biol Rep 2021; 49:2335-2344. [PMID: 34817775 DOI: 10.1007/s11033-021-06967-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/17/2021] [Indexed: 12/18/2022]
Abstract
Health and disease risk in the adulthood are known to be affected by the early developmental environment. Kidney diseases are one of these diseases, and kidneys are altered both structurally and functionally by adverse pre- and perinatal events. The most known structural change is low nephron number seen in subjects born low birth weight and/or preterm. In various animal models of intrauterine growth restriction (IUGR), one of the causes of low birth weight, the mechanism of low nephron number was investigated. While apoptosis of metanephric mesenchyme has been suggested to be the cause, I showed that suppression of ureteric branching, global DNA methylation, and caspase-3 activity also contributes to the mechanism. Other structural changes caused by adverse fetal and neonatal environments include peritubular and glomerular capillary rarefaction and low podocyte endowment. These are aggravated by postnatal development of focal glomerulosclerosis and tubulointerstitial fibrosis that result from low nephron number. Functional changes can be seen in tubules, endothelium, renin-angiotensin system, sympathetic nervous system, oxidative stress, and others. As an example, I reported that aggravated nitrosative stress in a rat IUGR model resulted in more severe tubular necrosis and tubulointerstitial fibrosis after unilateral ureteral obstruction. The mechanism of various functional changes needs to be clarified but may be explained by epigenetic modifications.
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Affiliation(s)
- Midori Awazu
- Department of Pediatrics, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
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Voggel J, Lubomirov L, Lechner F, Fink G, Nüsken E, Wohlfarth M, Pfitzer G, Shah-Hosseini K, Hellmich M, Alejandre Alcázar MA, Dötsch J, Nüsken KD. Vascular tone regulation in renal interlobar arteries of male rats is dysfunctional after intrauterine growth restriction. Am J Physiol Renal Physiol 2021; 321:F93-F105. [PMID: 34056927 DOI: 10.1152/ajprenal.00653.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
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.
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Affiliation(s)
- Jenny Voggel
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Lubomir Lubomirov
- Institute of Vegetative Physiology, University of Cologne, Cologne, Germany
| | - Felix Lechner
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Gregor Fink
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Eva Nüsken
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Maria Wohlfarth
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Gabriele Pfitzer
- Institute of Vegetative Physiology, University of Cologne, Cologne, Germany
| | - Kija Shah-Hosseini
- Institute of Medical Statistics and Computational Biology, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Martin Hellmich
- Institute of Medical Statistics and Computational Biology, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Miguel A Alejandre Alcázar
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Faculty of Medicine and University Hospital Cologne, Cologne Excellence Cluster for Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, Germany.,Institute for Lung Health (ILH), University of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Gießen, Germany
| | - Jörg Dötsch
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Kai-Dietrich Nüsken
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
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10
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Developmental programming of cardiovascular function: a translational perspective. Clin Sci (Lond) 2021; 134:3023-3046. [PMID: 33231619 DOI: 10.1042/cs20191210] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/07/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022]
Abstract
The developmental origins of health and disease (DOHaD) is a concept linking pre- and early postnatal exposures to environmental influences with long-term health outcomes and susceptibility to disease. It has provided a new perspective on the etiology and evolution of chronic disease risk, and as such is a classic example of a paradigm shift. What first emerged as the 'fetal origins of disease', the evolution of the DOHaD conceptual framework is a storied one in which preclinical studies played an important role. With its potential clinical applications of DOHaD, there is increasing desire to leverage this growing body of preclinical work to improve health outcomes in populations all over the world. In this review, we provide a perspective on the values and limitations of preclinical research, and the challenges that impede its translation. The review focuses largely on the developmental programming of cardiovascular function and begins with a brief discussion on the emergence of the 'Barker hypothesis', and its subsequent evolution into the more-encompassing DOHaD framework. We then discuss some fundamental pathophysiological processes by which developmental programming may occur, and attempt to define these as 'instigator' and 'effector' mechanisms, according to their role in early adversity. We conclude with a brief discussion of some notable challenges that hinder the translation of this preclinical work.
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11
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Hsu CN, Tain YL. Targeting the Renin-Angiotensin-Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins. Int J Mol Sci 2021; 22:ijms22052298. [PMID: 33669059 PMCID: PMC7956566 DOI: 10.3390/ijms22052298] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 02/21/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.
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Affiliation(s)
- Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan;
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Correspondence: ; Tel.: +886-975-056-995; Fax: +886-7733-8009
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12
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Nüsken E, Voggel J, Fink G, Dötsch J, Nüsken KD. Impact of early-life diet on long-term renal health. Mol Cell Pediatr 2020; 7:17. [PMID: 33269431 PMCID: PMC7710776 DOI: 10.1186/s40348-020-00109-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/13/2020] [Indexed: 12/15/2022] Open
Abstract
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.
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Affiliation(s)
- Eva Nüsken
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
| | - Jenny Voggel
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Gregor Fink
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Jörg Dötsch
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Kai-Dietrich Nüsken
- Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
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13
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Wood-Bradley RJ, Henry SL, Barrand S, Giot A, Eipper L, Bertram JF, Cullen-McEwen LA, Armitage JA. Analysis of structure and gene expression in developing kidneys of male and female rats exposed to low protein diets in utero. Anat Rec (Hoboken) 2020; 303:2657-2667. [PMID: 32567250 DOI: 10.1002/ar.24417] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/24/2019] [Accepted: 01/17/2020] [Indexed: 01/10/2023]
Abstract
A maternal low protein (LP) diet in rodents often results in low nephron endowment and renal pathophysiology in adult life, with outcomes often differing between male and female offspring. Precisely how a maternal LP diet results in low nephron endowment is unknown. We conducted morphological and molecular studies of branching morphogenesis and nephrogenesis to identify mechanisms and timepoints that might give rise to low nephron endowment. Sprague-Dawley rats were fed a normal protein (19.4% protein, NP) or LP (9% protein) diet for 3 weeks prior to mating and throughout gestation. Embryonic day 14.25 (E14.25) kidneys from males and females were either cultured for 2 days after which branching morphogenesis was quantified, or frozen for gene expression analysis. Real-time PCR was used to quantify expression of key nephrogenesis and branching morphogenesis genes at E14.25 and 17.25. At E17.25, nephron number was determined in fixed tissue. There was no effect of either maternal diet or sex on branching morphogenesis. Nephron number at E17.25 was 14% lower in male and female LP offspring than in NP controls. At E14.25 expression levels of genes involved in branching morphogenesis (Gfrα1, Bmp4, Gdnf) and nephrogenesis (Hnf4a, Pax2, Wnt4) were similar in the dietary groups, but significant differences between sexes were identified. At E17.25, expression of Gfrα1, Gdnf, Bmp4, Pax2 and Six2 was lower in LP offspring than NP offspring, in both male and female offspring. These findings provide new insights into how a LP diet leads to low nephron endowment and renal sexual dimorphism.
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Affiliation(s)
- Ryan J Wood-Bradley
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.,Department of Anatomy and Developmental Biology, and Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
| | - Sarah L Henry
- Department of Anatomy and Developmental Biology, and Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.,Mater Research Institute, The University of Queensland, Brisbane, Australia
| | - Sanna Barrand
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Anais Giot
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Luke Eipper
- Department of Anatomy and Developmental Biology, and Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
| | - John F Bertram
- Department of Anatomy and Developmental Biology, and Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
| | - Luise A Cullen-McEwen
- Department of Anatomy and Developmental Biology, and Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
| | - James A Armitage
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.,Department of Anatomy and Developmental Biology, and Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
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Gobetto MN, Mendes Garrido Abregú F, Caniffi C, Veiras L, Elesgaray R, Gironacci M, Tomat AL, Arranz C. Fetal and postnatal zinc restriction: sex differences in the renal renin-angiotensin system of newborn and adult Wistar rats. J Nutr Biochem 2020; 81:108385. [PMID: 32388253 DOI: 10.1016/j.jnutbio.2020.108385] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 03/05/2020] [Accepted: 03/26/2020] [Indexed: 02/07/2023]
Abstract
This study aimed to evaluate renal morphology and the renal renin-angiotensin system in 6- and 81-day-old male and female offspring exposed to zinc deficiency during fetal life, lactation and/or postnatal growth. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. Afterwards, offspring were fed a low- or a control zinc diet until 81 days of life. In 6- and/or 81-day-old offspring, we evaluated systolic blood pressure, renal morphology, renal angiotensin II and angiotensin 1-7 concentration, and AT1 and AT2 receptors and angiotensin-converting enzymes protein and/or mRNA expression. At 6 days, zinc-deficient male offspring showed decreased glomerular filtration areas, remodelling of renal arteries, greater number of renal apoptotic cells, increased levels of Angiotensin II, higher Angiotensin II/Angiotensin 1-7 ratio and increased angiotensin-converting enzyme 1, AT1 and AT2 receptors mRNA and/or protein expression. Exacerbation of the renal Ang II/AT1 receptor axis and remodelling of renal arteries were also observed in adult zinc-deficient male offspring. An adequate zinc diet during post-weaning life did not improve all the alterations induced by zinc deficiency in early stages of development. Female offspring would appear to be less sensitive to zinc deficiency with no increase in blood pressure or significant alterations in renal morphology and the renin-angiotensin system. Moderate zinc deficiency during critical periods of prenatal and postnatal development leads to early morphological renal alterations and to permanent and long-term changes in the renal renin-angiotensin system that could predispose to renal and cardiovascular diseases in adult life.
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Affiliation(s)
- María Natalia Gobetto
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Junín 956, Piso 7, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, Piso 2, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina
| | - Facundo Mendes Garrido Abregú
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Junín 956, Piso 7, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, Piso 2, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina
| | - Carolina Caniffi
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Junín 956, Piso 7, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, Piso 2, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina
| | - Luciana Veiras
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Junín 956, Piso 7, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, Piso 2, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Davis Research Bldg., Rm. 2007.110N, George Burns Rd., Los Angeles, CA 90048
| | - Rosana Elesgaray
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Junín 956, Piso 7, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, Piso 2, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina
| | - Mariela Gironacci
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica, Junín 956, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Junín 956, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina
| | - Analía Lorena Tomat
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Junín 956, Piso 7, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, Piso 2, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina.
| | - Cristina Arranz
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Junín 956, Piso 7, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina; CONICET, Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, Piso 2, CP 1113, Ciudad Autónoma de Buenos Aires, Argentina
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15
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Chinese famine exposure in infancy and metabolic syndrome in adulthood: results from the China health and retirement longitudinal study. Eur J Clin Nutr 2018; 73:724-732. [PMID: 29844493 DOI: 10.1038/s41430-018-0211-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 05/02/2018] [Accepted: 05/07/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND/OBJECTIVES To explore the association between famine exposure in early life and the risk of metabolic syndrome in the Chinese adults. SUBJECTS/METHODS A total of 2148 participants aged 50s were selected from a large national epidemiological survey in the China. The logistic regression models were used to analyze the association between famine exposure in early life and risk of metabolic syndrome in adulthood. RESULTS The prevalence of metabolic syndrome among individuals in the preschool exposed group, infant exposed group, fetal exposed group, and the non-exposed group was 37.9, 43.5, 37.5, and 34.0%, respectively. The prevalence of metabolic syndrome in the infant exposed group was significantly higher than the non-exposed group (43.5 vs. 34.0%, P = 0.006). Compared with the non-exposed group, individuals who exposed to the famine in infancy significantly increased the risk of metabolic syndrome (OR = 1.83; 95% CI: 1.24, 2.70) after adjusting for gender, smoking status, drinking status, physical activity, and the educational levels of participants and their parents. However, similar results were not observed in the fetal (OR = 1.25; 95% CI: 0.89, 1.74) or the preschool (OR = 1.30; 95% CI: 0.97, 1.75) exposed groups. CONCLUSIONS The Great China famine exposure during infancy was linked with the elevated risk of metabolic syndrome in adults aged 50s, which provided further evidence for the developmental origins hypothesis.
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16
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Baum M. Role of renal sympathetic nerve activity in prenatal programming of hypertension. Pediatr Nephrol 2018; 33:409-419. [PMID: 27001053 DOI: 10.1007/s00467-016-3359-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 02/15/2016] [Accepted: 02/18/2016] [Indexed: 12/30/2022]
Abstract
Prenatal insults, such as maternal dietary protein deprivation and uteroplacental insufficiency, lead to small for gestational age (SGA) neonates. Epidemiological studies from many different parts of the world have shown that SGA neonates are at increased risk for hypertension and early death from cardiovascular disease as adults. Animal models, including prenatal administration of dexamethasone, uterine artery ligation and maternal dietary protein restriction, result in SGA neonates with fewer nephrons than controls. These models are discussed in this educational review, which provides evidence that prenatal insults lead to altered sodium transport in multiple nephron segments. The factors that could result in increased sodium transport are discussed, focusing on new information that there is increased renal sympathetic nerve activity that may be responsible for augmented renal tubular sodium transport. Renal denervation abrogates the hypertension in programmed rats but has no effect on control rats. Other potential factors that could cause hypertension in programmed rats, such as the renin-angiotensin system, are also discussed.
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Affiliation(s)
- Michel Baum
- Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Building, Dallas, TX, 75390-9063, USA. .,Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
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17
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Abstract
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.
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Affiliation(s)
- Eva Nüsken
- Pediatric Nephrology, Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Jörg Dötsch
- Pediatric Nephrology, Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Lutz T Weber
- Pediatric Nephrology, Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Kai-Dietrich Nüsken
- Pediatric Nephrology, Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
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18
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Richter VFI, 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; 43:135-41. [PMID: 26475203 DOI: 10.1111/1440-1681.12505] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 09/21/2015] [Accepted: 10/12/2015] [Indexed: 11/27/2022]
Abstract
The intrauterine environment is critical for the development of the foetus. Barker and colleagues were the first to identify that adverse perturbations during foetal development are associated with an increased risk of developing diseases in adulthood, including cardiorenal disease. Specifically for the kidney, perturbations in utero can lead to nephron deficits and renal dysfunction by a number of mechanisms. Altered programming of nephron number is associated with an increased risk of developing kidney disease via glomerular hypertrophy and reduced vasodilative capacity of the renal blood vessels; both of which would contribute to hypertension in adulthood, with males being more susceptible to disease outcomes. Additionally, alterations in the renin-angiotensin system (RAS) such as an upregulation or downregulation of specific receptors, depending on the nature of the insult, have also been implicated in the development of renal dysfunction. Sex-specific differences in the expression of the RAS during late gestation and in the early postnatal environment have also been identified. Extensive research has demonstrated that both uteroplacental insufficiency and maternal malnutrition alter renal development in utero. Equally, exposure to maternal diabetes and maternal obesity during development are also associated with an increased risk of developing renal disease, however, the mechanism behind this association is poorly understood. Therefore, identifying the link between an adverse intrauterine environment and the programmed kidney disease risk in adulthood may facilitate the development of strategies to alleviate the epidemics of cardiorenal disease worldwide, in addition to understanding why males are more susceptible to adult-onset cardiovascular diseases.
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Affiliation(s)
- V F I Richter
- Department of Physiology, The University of Melbourne, Parkville, Vic., Australia
| | - J F Briffa
- Department of Physiology, The University of Melbourne, Parkville, Vic., Australia
| | - K M Moritz
- School of Biomedical Sciences, University of Queensland, St. Lucia, Qld, Australia
| | - M E Wlodek
- Department of Physiology, The University of Melbourne, Parkville, Vic., Australia
| | - D H Hryciw
- Department of Physiology, The University of Melbourne, Parkville, Vic., Australia
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Wang Z, Li C, Yang Z, Zou Z, Ma J. Infant exposure to Chinese famine increased the risk of hypertension in adulthood: results from the China Health and Retirement Longitudinal Study. BMC Public Health 2016; 16:435. [PMID: 27225778 PMCID: PMC4880986 DOI: 10.1186/s12889-016-3122-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 05/17/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Early-life developmental adaptations in response to severe malnutrition may play a crucial role in susceptibility to hypertension. This study aimed to explore the associations between exposure to the Chinese famine (1959-1961) at fetal, infant and preschool stages during fetal life or childhood and the risk of hypertension in adulthood. METHODS We used the data of 1,966 adults born between 1956 and 1964 in selected families from the China Health and Retirement Longitudinal Study (CHARLS) national survey. RESULTS Prevalence of hypertension among adults in non-exposed, fetal-exposed, infant-exposed, and preschool-exposed cohorts was 18.9, 20.7, 28.7, and 23.4 %, respectively. In severely affected famine areas, only infant-exposed cohort had a significant increased risk of hypertension compared with non-exposed cohort (OR 2.12; 95 % CI 1.19, 3.79; P = 0.011), and the significance remained after adjusted gender, smoking, and drinking (OR 2.11; 95 % CI 1.18, 3.77; P = 0.012). After stratification by BMI and economic status, the risk of hypertension was higher for subjects with BMI ≥ 24 kg/m(2)(OR 2.09; 95 % CI 1.09, 4.01; P = 0.026) or high economic status(OR 2.26; 95 % CI 1.19, 4.31; P = 0.013) than those with BMI < 24 kg/m(2)(OR 1.65; 95 % CI 0.71, 3.83; P = 0.246) or low economic status (OR 2.18; 95 % CI 1.14, 4.18; P = 0.019) in infant-exposed cohort of severely affected famine areas. However, there was no consistent association observed in less severely affected area or other exposed cohorts in severely affected areas. CONCLUSIONS Infanthood exposed to famine might increase the risk of hypertension in adulthood, and a postnatal 'rich' nutrient environment further increased the risk.
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Affiliation(s)
- Zhenghe Wang
- Institute of Child and Adolescent Health, School of Public Health, Peking University Health Science Center, No 38 Xue Yuan Road, Haidian District, Beijing, 100191, China
| | - Changwei Li
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
| | - Zhongping Yang
- Institute of Child and Adolescent Health, School of Public Health, Peking University Health Science Center, No 38 Xue Yuan Road, Haidian District, Beijing, 100191, China
| | - Zhiyong Zou
- Institute of Child and Adolescent Health, School of Public Health, Peking University Health Science Center, No 38 Xue Yuan Road, Haidian District, Beijing, 100191, China.
| | - Jun Ma
- Institute of Child and Adolescent Health, School of Public Health, Peking University Health Science Center, No 38 Xue Yuan Road, Haidian District, Beijing, 100191, China.
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20
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Perrone S, Santacroce A, Picardi A, Buonocore G. Fetal programming and early identification of newborns at high risk of free radical-mediated diseases. World J Clin Pediatr 2016; 5:172-181. [PMID: 27170927 PMCID: PMC4857230 DOI: 10.5409/wjcp.v5.i2.172] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 10/30/2015] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Nowadays metabolic syndrome represents a real outbreak affecting society. Paradoxically, pediatricians must feel involved in fighting this condition because of the latest evidences of developmental origins of adult diseases. Fetal programming occurs when the normal fetal development is disrupted by an abnormal insult applied to a critical point in intrauterine life. Placenta assumes a pivotal role in programming the fetal experience in utero due to the adaptive changes in structure and function. Pregnancy complications such as diabetes, intrauterine growth restriction, pre-eclampsia, and hypoxia are associated with placental dysfunction and programming. Many experimental studies have been conducted to explain the phenotypic consequences of fetal-placental perturbations that predispose to the genesis of metabolic syndrome, obesity, diabetes, hyperinsulinemia, hypertension, and cardiovascular disease in adulthood. In recent years, elucidating the mechanisms involved in such kind of process has become the challenge of scientific research. Oxidative stress may be the general underlying mechanism that links altered placental function to fetal programming. Maternal diabetes, prenatal hypoxic/ischaemic events, inflammatory/infective insults are specific triggers for an acute increase in free radicals generation. Early identification of fetuses and newborns at high risk of oxidative damage may be crucial to decrease infant and adult morbidity.
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21
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Lee JH, Lee H, Lee SM, Kang PJ, Kim KC, Hong YM. Changes of blood pressure, abdominal visceral fat tissue and gene expressions in fetal programming induced rat model after amlodipine-losartan combination treatment. Clin Hypertens 2016; 22:12. [PMID: 27051525 PMCID: PMC4820991 DOI: 10.1186/s40885-016-0046-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 01/29/2016] [Indexed: 01/05/2023] Open
Abstract
Background There are a number of complications that can occur if there is under-nutrition during pregnancy followed by a period of rapid catch-up growth, including a higher chance of adult obesity, insulin resistance and hypertriglyceridemia. The purposes of this study were to investigate the effects of fetal under-nutrition during late pregnancy and lactation on blood pressure, visceral fat tissue, gene expressions and to evaluate changes after amlodipine- losartan combination treatment. Methods The rats were divided into three groups: the control (C) group, the food restriction (FR: 50 % food restricted diet) group, and the CX group, which was treated with Cozaar XQ (amlodipine- losartan combination drug) in FR rats from postnatal 4 to 20 weeks. Masson’s trichrome staining was performed in the heart tissues. The amount of abdominal visceral fat tissues was measured. Western blot analysis such as angiotensin converting enzyme (ACE), angiotensin II receptor type IA (ATIA), troponin I (Tn I) and endothelial nitric oxide synthase (eNOS) were performed. Results Body weights were significantly higher in the FR group compared with the C group at weeks 8 and 20 and lower in the CX group at week 20. Blood pressure was significantly higher in the FR group compared with the C group at week 20 and lower in the CX group at weeks 12 and 20. The amount of abdominal visceral fat was significantly higher in the FR group compared with the C group at weeks 8, 12 and 20 and significantly lower in the CX group at weeks 16 and 20. Protein expression of ATIA and eNOS were significantly reduced in the CX group at weeks 16 and 20. ACE was significantly reduced in the CX group at week 20 and Tn I was significantly reduced in the CX group at week 16. Conclusions When there is fetal under-nutrition during pregnancy, it leads to obesity, high blood pressure, hypertriglyceridemia and several gene changes in offspring. Amlodipine-losartan combination treatment was able to lower obesity, hypertension, hypertriglyceridemia and several gene changes in rats suffering from fetal under-nutrition during pregnancy.
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Affiliation(s)
- Ji Hyen Lee
- Department of Pediatrics, Ewha Womans University, 911-1, Mokdong, YangCheon-Ku, Seoul, South Korea
| | - Hyeryon Lee
- Department of Pediatrics, Ewha Womans University, 911-1, Mokdong, YangCheon-Ku, Seoul, South Korea
| | - Sang Mi Lee
- Department of Pediatrics, Ewha Womans University, 911-1, Mokdong, YangCheon-Ku, Seoul, South Korea
| | - Pil Je Kang
- Department of Thoracic and Cardiovascular Surgery, Ewha Womans University, Seoul, South Korea
| | - Kwan Chang Kim
- Department of Thoracic and Cardiovascular Surgery, Ewha Womans University, Seoul, South Korea
| | - Young Mi Hong
- Department of Pediatrics, Ewha Womans University, 911-1, Mokdong, YangCheon-Ku, Seoul, South Korea
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Abstract
PURPOSE OF REVIEW Perinatal programming of renal function reflects the epigenetic alteration of genetically determined development by environmental factors. These include intrauterine malnutrition, pre and postnatal overnutrition, glucocorticoids, and certain toxins such as smoking. This review aims to summarize the most important findings. RECENT FINDINGS Human studies may show an increased susceptibility toward the general prevalence of renal failure in already small for gestational age children and adolescents. In particular, glomerular diseases present with a more severe clinical course. Partially related, partially independently, arterial hypertension is found in this at-risk group. The findings can mostly be confirmed in animal models. Both intrauterine nutrient deprived and overfed rodents show a tendency toward developing glomerulosclerosis and other renal disorders. Animal studies attempt to imitate clinical conditions, however, there are difficulties in transferring the findings to the human setting. The reduction of nephron number, especially in intrauterine growth-restricted humans and animals, is one mechanism of perinatal programming in the kidneys. In addition, vascular and endocrine alterations are prevalent. The molecular changes behind these mechanisms include epigenetic changes such as DNA-methylation, microRNAs, and histone modifications. SUMMARY Future research will have to establish clinical studies with clear and well defined inclusion criteria which also reflect prenatal life. The use of transgenic animal models might help to obtain a deeper insight into the underlying mechanisms.
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Morton JS, Cooke CL, Davidge ST. In Utero Origins of Hypertension: Mechanisms and Targets for Therapy. Physiol Rev 2016; 96:549-603. [DOI: 10.1152/physrev.00015.2015] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The developmental origins of health and disease theory is based on evidence that a suboptimal environment during fetal and neonatal development can significantly impact the evolution of adult-onset disease. Abundant evidence exists that a compromised prenatal (and early postnatal) environment leads to an increased risk of hypertension later in life. Hypertension is a silent, chronic, and progressive disease defined by elevated blood pressure (>140/90 mmHg) and is strongly correlated with cardiovascular morbidity/mortality. The pathophysiological mechanisms, however, are complex and poorly understood, and hypertension continues to be one of the most resilient health problems in modern society. Research into the programming of hypertension has proposed pharmacological treatment strategies to reverse and/or prevent disease. In addition, modifications to the lifestyle of pregnant women might impart far-reaching benefits to the health of their children. As more information is discovered, more successful management of hypertension can be expected to follow; however, while pregnancy complications such as fetal growth restriction, preeclampsia, preterm birth, etc., continue to occur, their offspring will be at increased risk for hypertension. This article reviews the current knowledge surrounding the developmental origins of hypertension, with a focus on mechanistic pathways and targets for therapeutic and pharmacologic interventions.
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Affiliation(s)
- Jude S. Morton
- Departments of Obstetrics and Gynaecology and of Physiology, University of Alberta, Edmonton, Canada; Women and Children's Health Research Institute, Edmonton, Canada; and Cardiovascular Research Centre, Edmonton, Canada
| | - Christy-Lynn Cooke
- Departments of Obstetrics and Gynaecology and of Physiology, University of Alberta, Edmonton, Canada; Women and Children's Health Research Institute, Edmonton, Canada; and Cardiovascular Research Centre, Edmonton, Canada
| | - Sandra T. Davidge
- Departments of Obstetrics and Gynaecology and of Physiology, University of Alberta, Edmonton, Canada; Women and Children's Health Research Institute, Edmonton, Canada; and Cardiovascular Research Centre, Edmonton, Canada
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Intapad S, Ojeda NB, Varney E, Royals TP, Alexander BT. Sex-Specific Effect of Endothelin in the Blood Pressure Response to Acute Angiotensin II in Growth-Restricted Rats. Hypertension 2015; 66:1260-6. [PMID: 26459423 DOI: 10.1161/hypertensionaha.115.06257] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 09/21/2015] [Indexed: 01/18/2023]
Abstract
The renal endothelin system contributes to sex differences in blood pressure with males demonstrating greater endothelin type-A receptor-mediated responses relative to females. Intrauterine growth restriction programs hypertension and enhance renal sensitivity to acute angiotensin II in male growth-restricted rats. Endothelin is reported to work synergistically with angiotensin II. Thus, this study tested the hypothesis that endothelin augments the blood pressure response to acute angiotensin II in male growth-restricted rats. Systemic and renal hemodynamics were determined in response to acute angiotensin II (100 mg/kg per minute for 30 minutes) with and without the endothelin type-A receptor antagonist, Atrasentan (ABT-627; 10 ng/kg per minute for 30 minutes), in rats pretreated with enalapril (250 mg/L for 1 week) to normalize the endogenous renin-angiotensin system. Endothelin type-A receptor blockade reduced angiotensin II-mediated increases in blood pressure in male control and male growth-restricted rats. Endothelin type-A receptor blockade also abolished hyper-responsiveness to acute angiotensin II in male growth-restricted rats. Yet, blood pressure remained significantly elevated above baseline after endothelin type-A receptor blockade, suggesting that factors in addition to endothelin contribute to the basic angiotensin II-induced pressor response in male rats. We also determined sex-specific effects of endothelin on acute angiotensin II-mediated hemodynamic responses. Endothelin type-A receptor blockade did not reduce acute angiotensin II-mediated increases in blood pressure in female control or growth-restricted rats, intact or ovariectomized. Thus, these data suggest that endothelin type-A receptor blockade contributes to hypersensitivity to acute angiotensin II in male growth-restricted rats and further supports the sex-specific effect of endothelin on blood pressure.
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Affiliation(s)
- Suttira Intapad
- Department of Pediatrics (N.B.O.), Department of Physiology and Biophysics (S.I., N.B.O., E.V., T.P.R., B.T.A.), and the Center for Developmental Disorders Research (S.I., N.B.O., B.T.A.), University of Mississippi Medical Center, Jackson
| | - Norma B Ojeda
- Department of Pediatrics (N.B.O.), Department of Physiology and Biophysics (S.I., N.B.O., E.V., T.P.R., B.T.A.), and the Center for Developmental Disorders Research (S.I., N.B.O., B.T.A.), University of Mississippi Medical Center, Jackson
| | - Elliott Varney
- Department of Pediatrics (N.B.O.), Department of Physiology and Biophysics (S.I., N.B.O., E.V., T.P.R., B.T.A.), and the Center for Developmental Disorders Research (S.I., N.B.O., B.T.A.), University of Mississippi Medical Center, Jackson
| | - Thomas P Royals
- Department of Pediatrics (N.B.O.), Department of Physiology and Biophysics (S.I., N.B.O., E.V., T.P.R., B.T.A.), and the Center for Developmental Disorders Research (S.I., N.B.O., B.T.A.), University of Mississippi Medical Center, Jackson
| | - Barbara T Alexander
- Department of Pediatrics (N.B.O.), Department of Physiology and Biophysics (S.I., N.B.O., E.V., T.P.R., B.T.A.), and the Center for Developmental Disorders Research (S.I., N.B.O., B.T.A.), University of Mississippi Medical Center, Jackson.
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Abstract
Type 2 diabetes (T2D) has become an increasingly challenging health burden due to its high morbidity, mortality, and heightened prevalence worldwide. Although dietary and nutritional imbalances have long been recognized as key risk factors for T2D, the underlying mechanisms remain unclear. The advent of nutritional systems biology, a field that aims to elucidate the interactions between dietary nutrients and endogenous molecular entities in disease-related tissues, offers unique opportunities to unravel the complex mechanisms underlying the health-modifying capacities of nutritional molecules. The recent revolutionary advances in omics technologies have particularly empowered this incipient field. In this review, we discuss the applications of multi-omics approaches toward a systems-level understanding of how dietary patterns and particular nutrients modulate the risk of T2D. We focus on nutritional studies utilizing transcriptomics, epigenomomics, proteomics, metabolomics, and microbiomics, and integration of diverse omics technologies. We also summarize the potential molecular mechanisms through which nutritional imbalances contribute to T2D pathogenesis based on these studies. Finally, we discuss the remaining challenges of nutritional systems biology and how the field can be optimized to further our understanding of T2D and guide disease management via nutritional interventions.
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Affiliation(s)
- Yuqi Zhao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095 USA
| | - Rio Elizabeth Barrere-Cain
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095 USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095 USA
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Increased systolic blood pressure in rat offspring following a maternal low-protein diet is normalized by maternal dietary choline supplementation. J Dev Orig Health Dis 2015; 3:342-9. [PMID: 25102263 DOI: 10.1017/s2040174412000256] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
An adverse prenatal environment may induce long-term metabolic consequences, in particular hypertension and cardiovascular disease. A maternal low-protein (LP) diet is well known to result in increased blood pressure (BP) in offspring. Choline has been shown to have direct BP-reducing effects in humans and animals. It has been suggested that endogenous choline synthesis via phosphatidylcholine is constrained during maternal LP exposure. The present study investigates the effect of choline supplementation to mothers fed a LP diet during pregnancy on systolic BP (SBP) in offspring as measured by tail-cuff plethysmography. Wistar rats were assigned to one of three diets to be fed ad libitum throughout pregnancy: (1) control diet (CONT, 20% protein); (2) an LP diet (9% protein); and (3) LP supplemented with choline (LP + C). Dams were fed the CONT diet throughout lactation and offspring were fed the CONT diet from weaning for the remainder of the trial. At postnatal day 150, SBP and retroperitoneal fat mass was significantly increased in LP offspring compared with CONT animals and was normalized in LP + C offspring. Effects of LP + C reduction in SBP were similar in both males and females. Plasma choline and phosphatidylcholine concentrations were not different across treatment groups, but maternal choline supplementation resulted in a significant reduction in homocysteine concentrations in LP + C offspring compared with LP and CONT animals. The present trial shows for the first time that maternal supplementation with dietary choline during periods of LP exposure can normalize increased SBP and fat mass observed in offspring in later life.
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27
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Pijacka W, Clifford B, Tilburgs C, Joles JA, Langley-Evans S, McMullen S. Protective role of female gender in programmed accelerated renal aging in the rat. Physiol Rep 2015; 3:3/4/e12342. [PMID: 25902787 PMCID: PMC4425955 DOI: 10.14814/phy2.12342] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The aging kidney exhibits a progressive decline in glomerular filtration rate, accompanied by inflammatory and oxidative damage. We hypothesized that accelerated, age-related progression of renal injury is ovarian hormones-dependant. To address this we used an established model of developmentally programmed accelerated renal aging in the rat, superimposed by ovariectomy to assess interactions between ovarian hormones and the aging process. Under our experimental conditions, we found that kidney function worsens with age, that is GFR reduces over 18 month analyzed time-course and this was worsened by fetal exposure to maternal low-protein diet and absence of estrogen. Reduction in GFR was followed by increases in albuminuria, proteinuria, inflammatory markers, and tissue carbonyls, all suggesting inflammatory response and oxidative stress. This was associated with changes in AGTR2 expression which was greater at 18 months of age compared to earlier time points, but in MLP offspring only. Our studies show an influence of ovarian hormones on programmed accelerated renal aging and the AGTR2 across the lifespan. The main findings are that ovariectomy is a risk factor for increased aging-related renal injury and that this and oxidative damage might be related to changes in AGTR2 expression.
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Affiliation(s)
- Wioletta Pijacka
- School of Physiology and Pharmacology, University of Bristol, Bristol, UK Division of Nutritional Sciences, School of Biosciences, University of Nottingham, Loughborough, UK
| | - Bethan Clifford
- Division of Nutritional Sciences, School of Biosciences, University of Nottingham, Loughborough, UK
| | - Chantal Tilburgs
- Department of Nephrology and Hypertension, University Medical Centre, Utrecht, The Netherlands
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Centre, Utrecht, The Netherlands
| | - Simon Langley-Evans
- Division of Nutritional Sciences, School of Biosciences, University of Nottingham, Loughborough, UK
| | - Sarah McMullen
- Division of Nutritional Sciences, School of Biosciences, University of Nottingham, Loughborough, UK
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Mecawi AS, Macchione AF, Nuñez P, Perillan C, Reis LC, Vivas L, Arguelles J. Developmental programing of thirst and sodium appetite. Neurosci Biobehav Rev 2015; 51:1-14. [DOI: 10.1016/j.neubiorev.2014.12.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 12/05/2014] [Accepted: 12/09/2014] [Indexed: 01/17/2023]
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Altered signaling pathways linked to angiotensin II underpin the upregulation of renal Na(+)-ATPase in chronically undernourished rats. Biochim Biophys Acta Mol Basis Dis 2014; 1842:2357-66. [PMID: 25283821 DOI: 10.1016/j.bbadis.2014.09.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 09/17/2014] [Accepted: 09/30/2014] [Indexed: 01/23/2023]
Abstract
This study has investigated the participation of altered signaling linked to angiotensin II (Ang II) that could be associated with increased Na(+) reabsorption in renal proximal tubules during chronic undernutrition. A multideficient chow for rats (basic regional diet, BRD) was used, which mimics several human diets widely taken in developing countries. The Vmax of the ouabain-resistant Na(+)-ATPase resident in the basolateral membranes increased >3-fold (P<0.001) accompanied by an increase in Na(+) affinity from 4.0 to 0.2mM (P<0.001). BRD rats had a >3-fold acceleration of the formation of phosphorylated intermediates in the early stage of the catalytic cycle (in the E1 conformation) (P<0.001). Immunostaining showed a huge increase in Ang II-positive cells in the cortical tubulointerstitium neighboring the basolateral membranes (>6-fold, P<0.001). PKC isoforms (α, ε, λ, ζ), Ang II type 1 receptors and PP2A were upregulated in BRD rats (in %): 55 (P<0.001); 35 (P<0.01); 125, 55, 11 and 30 (P<0.001). PKA was downregulated by 55% (P<0.001). With NetPhosK 1.0 and NetPhos 2.0, we detected 4 high-score (>0.70) regulatory phosphorylation sites for PKC and 1 for PKA in the primary sequence of the Na(+)-ATPase α-subunit, which are located in domains that are key for Na(+) binding and catalysis. Therefore, chronic undernutrition stimulates tubulointerstitial activity of Ang II and impairs PKC- and PKA-mediated regulatory phosphorylation, which culminates in an exaggerated Na(+) reabsorption across the proximal tubular epithelium.
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30
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Fetale und perinatale Programmierung der Nierenfunktion. GYNAKOLOGISCHE ENDOKRINOLOGIE 2014. [DOI: 10.1007/s10304-013-0593-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Renal molecular mechanisms underlying altered Na+ handling and genesis of hypertension during adulthood in prenatally undernourished rats. Br J Nutr 2014; 111:1932-44. [PMID: 24661554 DOI: 10.1017/s0007114513004236] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the present study, we investigated the development of hypertension in prenatally undernourished adult rats, including the mechanisms that culminate in dysfunctions of molecular signalling in the kidney. Dams were fed a low-protein multideficient diet throughout gestation with or without α-tocopherol during lactation. The time course of hypertension development followed in male offspring was correlated with alterations in proximal tubule Na+-ATPase activity, expression of angiotensin II (Ang II) receptors, and activity of protein kinases C and A. After the establishment of hypertension, Ang II levels, cyclo-oxygenase 2 (COX-2) and NADPH oxidase subunit expression, lipid peroxidation and macrophage infiltration were examined in renal tissue. Lipid peroxidation in undernourished rats, which was very intense at 60 d, decreased at 90 d and returned to control values by 150 d. During the prehypertensive phase, prenatally undernourished rats exhibited elevated renal Na+-ATPase activity, type 2 Ang II receptor down-regulation and altered protein kinase A:protein kinase C ratio. Stable late hypertension coexisted with highly elevated levels of Ang II-positive cells in the cortical tubulointerstitium, enhanced increase in the expression of p47phox (NADPH oxidase regulatory subunit), marked down-regulation of COX-2 expression, expanded plasma volume and decreased creatinine clearance. These alterations were reduced when the dams were given α-tocopherol during lactation. The offspring of well-nourished dams treated with α-tocopherol exhibited most of the alterations encountered in the offspring of undernourished dams not treated with α-tocopherol. Thus, alterations in proximal tubule Na+ transport, subcellular signalling pathways and reactive oxygen species handling in renal tissue underpin the development of hypertension.
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Gilbert JS, Cox LA, Mitchell G, Nijland MJ. Nutrient-restricted fetus and the cardio–renal connection in hypertensive offspring. Expert Rev Cardiovasc Ther 2014; 4:227-37. [PMID: 16509818 DOI: 10.1586/14779072.4.2.227] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
A suboptimal intrauterine environment has a number of deleterious effects on fetal development and postpartum health outcomes. Epidemiological studies on several human populations have linked socioeconomic status and low birth weight to an increased incidence of diseases such as hypertension, diabetes, obesity and cardiovascular disease. A growing number of experimental studies in a variety of animal models demonstrate that maternal stressors, such as nutrition and reduced uterine perfusion, affect the intrauterine milieu and result in increased blood pressure in offspring. Several mechanisms appear to contribute to hypertension, including vascular dysfunction and increased peripheral resistance, altered cardio-renal structure and alterations in cardio-renal function. Although many studies have characterized models of developmentally generated hypertension, few have begun to seek therapeutic modalities to ameliorate its incidence. This review discusses recent work that refines hypotheses linking a suboptimal intrauterine environment to cardiovascular and renal phenotypes that have increased susceptibility to cardiovascular disease and hypertension.
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Affiliation(s)
- Jeffrey S Gilbert
- Department of Obstetrics and Gynecology, Center for Pregnancy and Newborn Research, University of Texas Health Science Center, San Antonio, TX 78229, USA.
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The fetal origins of hypertension: a systematic review and meta-analysis of the evidence from animal experiments of maternal undernutrition. J Hypertens 2013; 30:2255-67. [PMID: 22990358 DOI: 10.1097/hjh.0b013e3283588e0f] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Numerous experiments in animals have been performed to investigate the effect of prenatal undernutrition on the development of hypertension in later life, with inconclusive results. We systematically reviewed animal studies examining the effects of maternal undernutrition on SBP, DBP, and mean arterial blood pressure (BP) in offspring. METHODS A search was performed in Medline and Embase to identify articles that reported on maternal undernutrition and hypertension in experimental animal studies. Summary estimates of the effect of undernutrition on SBP, DBP, and mean arterial BP were obtained through meta-analysis. RESULTS Of the 6151 articles identified, 194 were considered eligible after screening titles and abstracts. After detailed evaluation, 101 met the inclusion criteria and were included in the review. Both maternal general and protein undernutrition increased SBP [general undernutrition: 14.5 mmHg, 95% confidence interval (CI) 10.8-18.3; protein undernutrition: 18.9 mmHg, 95% CI 16.1-21.8] and mean arterial BP (general undernutrition: 5.0 mmHg, 95% CI 1.4-8.6; protein undernutrition: 10.5 mmHg, 95% CI 6.7-14.2). There was substantial heterogeneity in the results. DBP was increased by protein undernutrition (9.5 mmHg, 95% CI 2.6-16.3), whereas general undernutrition had no significant effect. CONCLUSION The results of this meta-analysis generally support the view that in animals, maternal undernutrition--both general and protein--results in increased SBP and mean arterial BP. DBP was only increased after protein undernutrition. The results depended strongly on the applied measurement technique and animal model.
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Reverte V, Tapia A, Baile G, Gambini J, Gíménez I, Llinas MT, Salazar FJ. Role of angiotensin II in arterial pressure and renal hemodynamics in rats with altered renal development: age- and sex-dependent differences. Am J Physiol Renal Physiol 2012; 304:F33-40. [PMID: 23097470 DOI: 10.1152/ajprenal.00424.2012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Numerous studies have demonstrated that angiotensin II (ANG II) is involved in hypertension and renal changes occurring as a consequence of an adverse event during renal development. However, it was unknown whether this involvement is sex and age dependent. This study examines whether the increments in arterial pressure (AP) and in the renal sensitivity to ANG II are sex and age dependent in rats with altered renal development. It also evaluates whether the ANG II effects are accompanied by increments in AT(1) receptors and oxidative stress. Experiments were performed in 3- to 4- and 10- to 11-mo-old rats treated with vehicle or an AT(1) receptor antagonist (ARAnp) during the nephrogenic period. ARAnp-treated rats were hypertensive, but an age-dependent rise in AP was only found in males. Three days of treatment with candesartan (7 mg·kg(-1)·day(-1)) led to a fall of AP that was greater (P < 0.05) in male than in female 10- to 11-mo-old ARAnp-treated rats. Oxidated proteins were elevated (P < 0.05), and the decrease in AP elicited by candesartan was reduced (P < 0.05) when these rats are also treated with tempol (18 mg·kg(-1)·day(-1)). Hypertension was not maintained by an elevation of AT(1) receptors in kidneys and mesenteric arteries. The acute renal hemodynamic response to ANG II (30 ng·kg(-1)·min(-1)) was similarly enhanced (P < 0.05) in both sexes of ARAnp-treated rats at 3-4 but not at 10-11 mo of age. Our results suggest that an adverse event during the nephrogenic period induces an ANG II-dependent increment in AP that is aggravated only in males during aging and that oxidative stress but not an increase in AT(1) receptor contributes to the rise in AP. This study also shows that the renal hemodynamic sensitivity to ANG II is transitorily enhanced in both sexes of rats with altered renal development.
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Affiliation(s)
- Virginia Reverte
- Dept. of Physiology, School of Medicine, Univ. of Murcia, Murcia, Spain
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Influence of angiotensin II type 1 receptor-associated protein on prenatal development and adult hypertension after maternal dietary protein restriction during pregnancy. ACTA ACUST UNITED AC 2012; 6:324-30. [DOI: 10.1016/j.jash.2012.07.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 07/05/2012] [Accepted: 07/05/2012] [Indexed: 11/20/2022]
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Influence of birth weight on the renal development and kidney diseases in adulthood: experimental and clinical evidence. Int J Nephrol 2012; 2012:608025. [PMID: 22778952 PMCID: PMC3385608 DOI: 10.1155/2012/608025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Revised: 04/18/2012] [Accepted: 05/02/2012] [Indexed: 01/21/2023] Open
Abstract
Several clinical and experimental studies support the hypothesis that foetal programming is an important determinant of nephropathy, hypertension, coronary heart disease, and type 2 diabetes during adulthood. In this paper, the renal repercussions of foetal programming are emphasised, and the physiopathological mechanisms are discussed. The programming of renal diseases is detailed based on the findings of kidney development and functional parameters.
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Sathishkumar K, Balakrishnan M, Chinnathambi V, Gao H, Yallampalli C. Temporal alterations in vascular angiotensin receptors and vasomotor responses in offspring of protein-restricted rat dams. Am J Obstet Gynecol 2012; 206:507.e1-10. [PMID: 22537420 DOI: 10.1016/j.ajog.2012.04.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 03/21/2012] [Accepted: 04/03/2012] [Indexed: 10/28/2022]
Abstract
OBJECTIVE Examine temporal alterations in vascular angiotensin II receptors (AT(1)R and AT(2)R) and determine vascular response to angiotensin II in growth-restricted offspring. STUDY DESIGN Offspring of pregnant rats fed low-protein (6%) and control (20%) diet were compared. RESULTS Prenatal protein restriction reprogrammed AT(1a)R messenger RNA expression in male rats' mesenteric arteries to cause 1.7- and 2.3-fold increases at 3 and 6 months of age associated with arterial pressure increases of 10 and 33 mm Hg, respectively; however, in female rats, increased AT(1a)R expression (2-fold) and arterial pressure (15 mm Hg) occurred only at 6 months. Prenatal protein restriction did not affect AT(2)R expression. Losartan abolished hypertension, suggesting that AT(1a)R plays a primary role in arterial pressure elevation. Vasoconstriction to angiotensin II was exaggerated in all protein-restricted offspring, with greater potency and efficacy in male rats. CONCLUSION Prenatal protein restriction increased vascular AT(1)R expression and vasoconstriction to angiotensin II, possibly contributing to programmed hypertension.
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The effect of hypoxia-induced intrauterine growth restriction on renal artery function. J Dev Orig Health Dis 2012; 3:333-41. [DOI: 10.1017/s2040174412000268] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The risk of developing cardiovascular diseases is known to begin before birth and the impact of the intrauterine environment on subsequent adult health is currently being investigated from many quarters. Following our studies demonstrating the impact of hypoxiain uteroand consequent intrauterine growth restriction (IUGR) on the rat cardiovascular system, we hypothesized that changes extend throughout the vasculature and alter function of the renal artery. In addition, we hypothesized that hypoxia induces renal senescence as a potential mediator of altered vascular function. We demonstrated that IUGR females had decreased responses to the adrenergic agonist phenylephrine (PE; pEC506.50 ± 0.05 controlv. 6.17 ± 0.09 IUGR,P< 0.05) and the endothelium-dependent vasodilator methylcholine (MCh;Emax89.8 ± 7.0% controlv. 41.0 ± 6.5% IUGR,P< 0.001). In IUGR females, this was characterised by increased basal nitric oxide (NO) modulation of vasoconstriction (PE pEC506.17 ± 0.09 IUGRv. 6.42 ± 0.08 in the presence of the NO synthase inhibitorN-nitro-l-arginine methyl ester hydrochloride (l-NAME;P< 0.01) but decreased activated NO modulation (no change in MCh responses in the presence ofl-NAME), respectively. In contrast, IUGR males had no changes in PE or MCh responses but demonstrated increased basal NO (PE pEC506.29 ± 0.06 IUGRv. 6.42 ± 0.12 plusl-NAME,P< 0.01) and activated NO (Emax37.8 ± 9.4% controlv. −0.8 ± 13.0% plusl-NAME,P< 0.05) modulation. No significant changes were found in gross kidney morphology, proteinuria or markers of cellular senescence in either sex. In summary, renal vascular function was altered by hypoxiain uteroin a sex-dependent manner but was unlikely to be mediated by premature renal senescence.
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Dötsch J, Plank C, Amann K. Fetal programming of renal function. Pediatr Nephrol 2012; 27:513-20. [PMID: 21298502 DOI: 10.1007/s00467-011-1781-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Revised: 12/09/2010] [Accepted: 12/15/2010] [Indexed: 01/10/2023]
Abstract
Results from large epidemiological studies suggest a clear relation between low birth weight and adverse renal outcome evident as early as during childhood. Such adverse outcomes may include glomerular disease, hypertension, and renal failure and contribute to a phenomenon called fetal programming. Other factors potentially leading to an adverse renal outcome following fetal programming are maternal diabetes mellitus, smoking, salt overload, and use of glucocorticoids during pregnancy. However, clinical data on the latter are scarce. Here, we discuss potential underlying mechanisms of fetal programming, including reduced nephron number via diminished nephrogenesis and other renal (e.g., via the intrarenal renin-angiotensin-aldosterone system) and non-renal (e.g., changes in endothelial function) alterations. It appears likely that the outcomes of fetal programming may be influenced or modified postnatally, for example, by the amount of nutrients given at critical times.
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Affiliation(s)
- Jörg Dötsch
- Department of Pediatrics, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
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Saito T, Musha Y, Miyakawa M, Itoh S, Ohtsuji M, Hanson MA, Takeda S. Angiotensin II receptor antagonist reduces subsequent uterine arterial dysfunction in pregnant offspring of protein-restricted rat dams. J Obstet Gynaecol Res 2012; 38:483-9. [DOI: 10.1111/j.1447-0756.2011.01737.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Alwasel SH, Ashton N. Segmental sodium reabsorption by the renal tubule in prenatally programmed hypertension in the rat. Pediatr Nephrol 2012; 27:285-93. [PMID: 21863227 DOI: 10.1007/s00467-011-1976-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Revised: 07/05/2011] [Accepted: 07/05/2011] [Indexed: 10/17/2022]
Abstract
Hypertension and renal dysfunction can be programmed in the rat by prenatal exposure to a low-protein (LP) diet. Expression of the renal thick ascending limb (TAL) sodium transporter NKCC2 is up-regulated, which has been predicted to result in greater sodium reabsorption. However, we have shown that LP rats excrete more not less sodium. The aim of this study was to determine whether the increased abundance of sodium:potassium:chloride (Na(+):K(+):2Cl(-)) co-transporter (NKCC2) leads to enhanced sodium uptake by the TAL. Pregnant Wistar rats were fed a control (18%) or LP (9%) diet. Amiloride (AM), bendroflumethiazide (BF), and furosemide (FUR) were administered acutely to male offspring at 4 weeks of age. Fractional excretion of sodium (FE(Na)) was significantly greater in vehicle-infused LP rats (3.0 ± 0.3%) compared with controls (1.7 ± 0.5, P < 0.01). FE(Na) by the LP proximal tubule did not differ from controls, whereas FE(Na) by the distal tubule was significantly greater (P < 0.01). These differences were abolished by the administration of AM + BF (equivalent to the outflow from the TAL) and AM + BF + FUR (equivalent to the outflow from the proximal tubule), suggesting that the increase in NKCC2 expression was not functional. However, during acute salt loading, the LP rat pressure natriuresis curve was shifted rightward, implying that raised systemic blood pressure is required to match urinary sodium excretion with dietary intake. These data suggest that renal sodium handling is impaired in the LP rat but that this is not due to increased NKCC2 expression.
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Affiliation(s)
- Saleh H Alwasel
- Fetal Programming of Diseases Research Chair, College of Science, King Saud University, PO Box 2455, Riyadh, 11451, Saudi Arabia.
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Prenatal programming of renal salt wasting resets postnatal salt appetite, which drives food intake in the rat. Clin Sci (Lond) 2011; 122:281-8. [DOI: 10.1042/cs20110266] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Sodium retention has been proposed as the cause of hypertension in the LP rat (offspring exposed to a maternal low-protein diet in utero) model of developmental programming because of increased renal NKCC2 (Na+/K+/2Cl− co-transporter 2) expression. However, we have shown that LP rats excrete more rather than less sodium than controls, leading us to hypothesize that LP rats ingest more salt in order to maintain sodium balance. Rats were fed on either a 9% (low) or 18% (control) protein diet during pregnancy; male and female offspring were studied at 4 weeks of age. LP rats of both sexes held in metabolism cages excreted more sodium and urine than controls. When given water to drink, LP rats drank more and ate more food than controls, hence sodium intake matched excretion. However, when given a choice between saline and water to drink, the total volume of fluid ingested by LP rats fell to control levels, but the volume of saline taken was significantly larger [3.8±0.1 compared with 8.8±1.3 ml/24 h per 100 g of body weight in control and LP rats respectively; P<0.001]. Interestingly food intake also fell to control levels. Total body sodium content and ECF (extracellular fluid) volumes were greater in LP rats. These results show that prenatal programming of renal sodium wasting leads to a compensatory increase in salt appetite in LP rats. We speculate that the need to maintain salt homoeostasis following malnutrition in utero stimulates greater food intake, leading to accelerated growth and raised BP (blood pressure).
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Otani L, Sugimoto N, Kaji M, Murai M, Chang SJ, Kato H, Murakami T. Role of the renin-angiotensin-aldosterone system in the enhancement of salt sensitivity caused by prenatal protein restriction in stroke-prone spontaneously hypertensive rats. J Nutr Biochem 2011; 23:892-9. [PMID: 21937213 DOI: 10.1016/j.jnutbio.2011.04.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 04/08/2011] [Accepted: 04/13/2011] [Indexed: 12/11/2022]
Abstract
We previously demonstrated that maternal protein restriction during pregnancy enhanced salt sensitivity and shortened life span in stroke-prone spontaneously hypertensive rats (SHRSP). The present study was conducted to investigate the participation of the renin-angiotensin-aldosterone system in the development of salt sensitivity in the offspring of dams fed a low-protein diet during pregnancy. We used SHRSP offspring from dams fed a 20% casein diet (CN) or a 9% casein diet (LP) during pregnancy. The CN and LP SHRSP offspring were further subdivided into tap-water-drinking and 1%-saline-drinking groups from the postnatal 10th week. A remarkable elevation in blood pressure in response to salt loading was observed in the LP SHRSP offspring. The protein levels of CYP11B2, an enzyme for aldosterone synthesis, were markedly elevated in response to salt loading in the kidneys of LP offspring. Treatment of the LP offspring with an aldosterone receptor antagonist prevented the blood pressure from elevating and lengthened the average life span in LP offspring in response to the drinking of 1% saline. No difference in the activity of angiotensin-converting enzyme or in the protein level of the angiotensin type 1 receptor was found between the CN and LP offspring in either the tap-water-drinking or saline-drinking conditions. In conclusion, the increment of aldosterone production in response to high-salt loading may contribute to the elevated salt sensitivity of the offspring of protein-restricted dams.
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Affiliation(s)
- Lila Otani
- Department of Food Science and Nutrition, Faculty of Agriculture, Kinki University, Nakamachi, Nara, Japan
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Singh RR, Moritz KM, Wintour EM, Jefferies AJ, Iqbal J, Bertram JF, Denton KM. Fetal uninephrectomy in male sheep alters the systemic and renal responses to angiotensin II infusion and AT1R blockade. Am J Physiol Renal Physiol 2011; 301:F319-26. [DOI: 10.1152/ajprenal.00139.2011] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Fetal uninephrectomy (uni-x) at 100 days of gestation results in compensatory nephrogenesis in the remaining kidney, resulting in a 30% reduction in total nephron number in male sheep. Recently, we showed that uni-x males at 6 mo of age have elevated arterial pressure, reduced renal blood flow (RBF), glomerular filtration rate (GFR), and low plasma renin levels (Singh R, Denton K, Bertram J, Jefferies A, Head G, Lombardo P, Schneider-Kolsky M, Moritz K. J Hypertens 27: 386–396, 2009; Singh R, Denton K, Jefferies A, Bertram J, Moritz K. Clin Sci (Lond) 118: 669–680, 2010). We hypothesized this was due to upregulation of the intrarenal renin-angiotensin system (RAS). In this study, renal responses to ANG II infusion and ANG II type 1 receptor (AT1R) blockade were examined in the same 6-mo-old male sheep. Uni-x animals had reduced levels of renal tissue and plasma renin and ANG II. Renal gene expression of renin, and gene and protein levels of AT1R and AT2R, were significantly lower in uni-x animals. In response to graded ANG II infusion, sham animals had the expected decrease in conscious RBF and GFR. Interestingly, the response was biphasic in uni-x sheep, with GFR initially decreasing, but then increasing at higher ANG II doses (34 ± 7%; Pgroup × treatment < 0.001), due to a paradoxical decrease in renal vascular resistance ( Pgroup × treatment < 0.001). In response to AT1R blockade, while GFR and RBF responded similarly between groups, there was a marked increase in sodium excretion in uni-x compared with sham sheep (209 ± 35 vs. 25 ± 12%; P < 0.001). In conclusion, in 6-mo-old male sheep born with a single kidney, these studies demonstrate that this is a low-renin form of hypertension, in which responses to ANG II are perturbed and the intrarenal RAS is downregulated.
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Affiliation(s)
| | - Karen M. Moritz
- School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia
| | - E. Marelyn Wintour
- Departments of 1Anatomy and Developmental Biology and
- Physiology, Monash University, Victoria, and
| | | | - Javed Iqbal
- Physiology, Monash University, Victoria, and
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Yim HE, Ha KS, Bae IS, Yoo KH, Hong YS, Lee JW. Postnatal early overnutrition dysregulates the intrarenal renin-angiotensin system and extracellular matrix-linked molecules in juvenile male rats. J Nutr Biochem 2011; 23:937-45. [PMID: 21752621 DOI: 10.1016/j.jnutbio.2011.04.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Revised: 01/17/2011] [Accepted: 04/20/2011] [Indexed: 12/22/2022]
Abstract
Overnutrition during the perinatal period has been associated with susceptibility to obesity and related comorbidities. We examined the effects of postnatal early overnutrition on the development of juvenile obesity and the associated renal pathophysiological changes. Three or 10 pups per mother from rat pup litters were assigned to either the overnutrition or control groups during the first 21 days of life. The effects of overfeeding were measured at 28 days. The smaller male litter pups were heavier than the controls between 4 and 28 days after birth (P<.05). By 28 days of age, the kidney weight per body weight ratio decreased in the small litter group (P<.05). Circulating leptin levels increased in the small litter rats (P<.05). Overnutrition had no effect on renal cell proliferation, apoptosis, macrophages and glomerulosclerosis. In the immunoblots and immunohistochemistry, renin and angiotensin II type (AT) 2 receptor expression increased in the overfed rats (P<.05). By contrast, the plasminogen activator inhibitor (PAI)-1 and matrix metalloproteinase (MMP)-9 expression decreased in the overnutrition group (P<.05). The AT 1 receptor, tissue inhibitor of MMP-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, osteopontin and adiponectin expression was not changed. Our data showed that postnatal early overfeeding led to hyperleptinemia, juvenile obesity and the acquired reset of renal maturation. Up-regulation of renin and AT2 and down-regulation of PAI-1 and MMP-9 might contribute to abnormal programming of renal growth in rats exposed to postnatal early overnutrition.
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Affiliation(s)
- Hyung Eun Yim
- Department of Pediatrics, College of Medicine, Korea University, Seoul, Korea
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Simeoni U, Ligi I, Buffat C, Boubred F. Adverse consequences of accelerated neonatal growth: cardiovascular and renal issues. Pediatr Nephrol 2011; 26:493-508. [PMID: 20938692 DOI: 10.1007/s00467-010-1648-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Revised: 07/12/2010] [Accepted: 07/26/2010] [Indexed: 12/13/2022]
Abstract
Epidemiological and experimental studies show that the risk of cardiovascular and metabolic diseases at adulthood is inversely related to the weight at birth. Although with less evidence, low birth weight has been suggested to increase the risk of chronic kidney disease (CKD). It is well established that the developmental programming of arterial hypertension and of renal disease involves in particular renal factors, especially nephron endowment, which is reduced in low birth weight and maternal diabetes situations. Experimental studies, especially in rodents, have demonstrated the long-term influence of postnatal nutrition and/or postnatal growth on cardiovascular, metabolic and renal functions, while human data are scarce on this issue. Vascular and renal diseases appear to have a "multihits" origin, with reduced nephron number the initial hit and rapid postnatal growth the second hit. This review addresses the current understanding of the role of the kidney, both as a mechanism and as a target, in the developmental origins of adult disease theory, with a particular focus on the long-term effects of postnatal growth and nutrition.
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Affiliation(s)
- Umberto Simeoni
- Division of Neonatology, Hôpital la Conception, Assistance Publique-Hôpitaux de Marseille, 147 Boulevard Baille, 13385, Marseille, France.
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Gwathmey TM, Shaltout HA, Rose JC, Diz DI, Chappell MC. Glucocorticoid-induced fetal programming alters the functional complement of angiotensin receptor subtypes within the kidney. Hypertension 2011; 57:620-6. [PMID: 21220702 PMCID: PMC3041840 DOI: 10.1161/hypertensionaha.110.164970] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
We examined the impact of fetal programming on the functional responses of renal angiotensin receptors. Fetal sheep were exposed in utero to betamethasone (BMX; 0.17 mg/kg) or control (CON) at 80 to 81 days gestation with full-term delivery. Renal nuclear and plasma membrane fractions were isolated from sheep age 1.0 to 1.5 years for receptor binding and fluorescence detection of reactive oxygen species (ROS) or nitric oxide (NO). Mean arterial blood pressure and blood pressure variability were significantly higher in the BMX-exposed adult offspring versus CON sheep. The proportion of nuclear AT(1) receptors sensitive to losartan was 2-fold higher (67 ± 6% vs 27 ± 9%; P<0.01) in BMX compared with CON. In contrast, the proportion of AT(2) sites was only one third that of controls (BMX, 25 ± 11% vs CON, 78 ± 4%; P<0.01), with a similar reduction in sites sensitive to the Ang-(1-7) antagonist D-Ala7-Ang-(1-7) with BMX exposure. Functional studies revealed that Ang II stimulated ROS to a greater extent in BMX than in CON sheep (16 ± 3% vs 6 ± 4%; P<0.05); however, NO production to Ang II was attenuated in BMX (26 ± 7% vs 82 ± 14%; P<0.05). BMX exposure was also associated with a reduction in the Ang-(1-7) NO response (75 ± 8% vs 131 ± 26%; P<0.05). We conclude that altered expression of angiotensin receptor subtypes may be one mechanism whereby functional changes in NO- and ROS-dependent signaling pathways may favor the sustained increase in blood pressure evident in fetal programming.
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Affiliation(s)
- TanYa M. Gwathmey
- Hypertension and Vascular Research Center, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
| | - Hossam A. Shaltout
- Hypertension and Vascular Research Center, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
| | - James C. Rose
- Center for Perinatal Research, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
| | - Debra I. Diz
- Hypertension and Vascular Research Center, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
| | - Mark C. Chappell
- Hypertension and Vascular Research Center, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
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Benz K, Campean V, Cordasic N, Karpe B, Neuhuber W, Mall G, Hartner A, Hilgers KF, Amann K. Early glomerular alterations in genetically determined low nephron number. Am J Physiol Renal Physiol 2011; 300:F521-30. [DOI: 10.1152/ajprenal.00490.2009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
An association between low nephron number and subsequent development of hypertension in later life has been demonstrated. The underlying pathomechanisms are unknown, but glomerular and postglomerular changes have been discussed. We investigated whether such changes are already present in prehypertensive “glial cell line-derived neurotrophic growth factor” heterozygous mice (GDNF+/−) with lower nephron number. Twenty-six-week-old mice [22 GDNF+/−, 29 C57B6 wild-type control (wt)] were used for in vivo experiments with intra-arterial and tail cuff blood pressure measurements. After perfusion fixation, kidneys were investigated with morphological, morphometric, stereological, and immunohistochemical techniques and TaqMan PCR analysis. As expected at this age, blood pressure was comparable between GDNF+/− and wt. Nephron number per kidney was significantly lower in GDNF+/− than in wt (−32.8%, P < 0.005), and mean glomerular volume was significantly higher (+49.5%, P < 0.001). Renal damage scores, glomerular and tubular proliferation, analysis of intrarenal arteries and peritubular capillaries, expression of relevant tubular transporter proteins, as well as gene expression of profibrotic, proinflammatory, or prohypertensive markers were not significantly different between GDNF+/− and wt. Compensatory glomerular hypertrophy in GDNF+/− was accompanied by higher numbers of endothelial and mesangial cells as well as PCNA-positive glomerular cells, whereas podocyte density was significantly reduced. Further electron microscopic analysis showed marked thickening of glomerular basement membrane. In conclusion, lower nephron number is associated with marked early glomerular structural changes, in particular lower capillary supply, reduced podocyte density, and thickened glomerular basement membrane, that may predispose to glomerular sclerosis.
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Affiliation(s)
| | | | | | | | | | - Gerhard Mall
- Department of Pathology, Hospital of Darmstadt, Darmstadt, Germany
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Musha Y, Itoh S, Miyakawa M, Ohtsuji M, Hanson MA, Kinoshita K, Takeda S. Vascular, renal and placental effects on pregnant offspring of protein-restricted rat dams. J Obstet Gynaecol Res 2011; 37:343-51. [PMID: 21272146 DOI: 10.1111/j.1447-0756.2010.01351.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
AIM Our previous study showed that a maternal low-protein diet induced hypertension and vascular dysfunction in rat offspring after day 175. In the present study, we hypothesized that these female offspring would develop hypertension in their own pregnancies even at ages less than 175 days because potential vascular dysfunction is exacerbated by the circulatory demands of pregnancy. MATERIAL AND METHODS Wistar rats were fed an isocaloric diet containing either 18% (control group) or 9% (low-protein group) casein throughout pregnancy. The female offspring were fed standard chow and mated between days 70 and 125. At the end of pregnancy, blood pressure was measured, and the uterine arteries were dissected and investigated with a wire myograph. RESULTS Placental weights were significantly lower in offspring of the low-protein group versus control. There were no significant differences in blood pressure. Renal expression of AT1 receptor mRNA was greater, and of AT2 receptor was less, in the low-protein group versus control. Vasoconstriction of uterine arteries to phenylephrine and U46619 was increased in the low-protein group, and vasodilatation to sodium nitroprusside was also increased. CONCLUSION Low-protein diet induces vascular effects on female offspring in their pregnancy, in terms of increased uterine artery vasoconstriction. This may be compensated for by increased sensitivity to nitric oxide (NO), maintaining blood pressure normal in the face of the demands of pregnancy. Such renal and vascular effects, combined with placental size, may transmit risk of vascular dysfunction to subsequent generations.
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Affiliation(s)
- Yuka Musha
- Department of Obstetrics and Gynecology, School of Medicine, Juntendo University, Tokyo, Japan.
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Abstract
Development of the kidney can be altered in utero in response to a suboptimal environment. The intrarenal factors that have been most well characterized as being sensitive to programming events are kidney mass/nephron endowment, the renin-angiotensin system, tubular sodium handling, and the renal sympathetic nerves. Newborns that have been subjected to an adverse intrauterine environment may thus begin life at a distinct disadvantage, in terms of renal function, at a time when the kidney must take over the primary role for extracellular fluid homeostasis from the placenta. A poor beginning, causing renal programming, has been linked to increased risk of hypertension and renal disease in adulthood. However, although a cause for concern, increasingly, evidence demonstrates that renal programming is not a fait accompli in terms of future cardiovascular and renal disease. A greater understanding of postnatal renal maturation and the impact of secondary factors (genes, sex, diet, stress, and disease) on this process is required to predict which babies are at risk of increased cardiovascular and renal disease as adults and to be able to devise preventative measures.
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Affiliation(s)
- Michelle M Kett
- Department of Physiology, Monash University, Clayton, Victoria, Australia
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