Vitamin A Deficiency Rats Research Articles

Vitamin A Status Modulates Epithelial Mesenchymal Transition in the Lung: The Role of Furin.

Vitamin A deficiency (VAD) induced TGF-β hyperactivation and reduced expression of cell adhesion proteins in the lung, suggesting that the disruption of retinoic acid (RA) signaling leads to epithelial-mesenchymal transition (EMT). To elucidate the role of lung vitamin A status in EMT, several EMT markers and the expression of the proprotein convertase furin, which activates TGF-β, were analyzed in two experimental models. Our in vivo model included control rats, VAD rats, and both control rats and VAD rats, treated with RA. For the in vitro studies, human bronchoalveolar epithelial cells treated with RA were used. Our data show that EMT and furin are induced in VAD rats. Furthermore, furin expression continues to increase much more markedly after treatment of VAD rats with RA. In control rats and cell lines, an acute RA treatment induced a significant increase in furin expression, concomitant with changes in EMT markers. A ChIP assay demonstrated that RA directly regulates furin transcription. These results emphasize the importance of maintaining vitamin A levels within the physiological range since both levels below and above this range can cause adverse effects that, paradoxically, could be similar. The role of furin in EMT is discussed.

Vitamin A deficiency from maternal gestation may contribute to autistic-like behaviors and gastrointestinal dysfunction in rats through the disrupted purine and tryptophan metabolism

Vitamin A deficiency (VAD) has been linked to autism spectrum disorder (ASD) in multiple studies, and autistic children with gastrointestinal (GI) symptoms have been found to have lower VA levels than those without GI symptoms. However, the exact mechanism by which VAD causes both core symptoms and GI symptoms in ASD is ill defined. We constructed VAD and vitamin A normal (VAN) rat models from maternal gestation onwards. Autism-related behaviors were tested using the open-field test and the three-chamber test, and GI function was assessed with the GI transit time, the colonic transit time and fecal water content. Untargeted metabolomic analysis on the prefrontal cortex (PFC) and fecal samples was performed. VAD rats displayed autistic-like behaviors and impaired GI function compared to VAN rats. Metabolic profiles of both PFC and feces from VAD and VAN rats were significantly different. The differential metabolites in both PFC and feces between the VAN and VAD rats were mostly enriched in the purine metabolic pathway. Moreover, the most significantly affected metabolic pathway in PFC of VAD rats was the phenylalanine, tyrosine and tryptophan biosynthesis pathway, and the most remarkably altered metabolic pathway in the feces of VAD rats was the tryptophan metabolism pathway. These results indicate that VAD starting from maternal gestation might be linked to core symptoms of ASD and its GI co-occurring disorders through the purine and tryptophan-related metabolism disorders.

Involvement of retinoic acid receptor α in the autistic-like behavior of rats with vitamin A deficiency by regulating neurexin 1 in the visual cortex: a mechanism study.

To study the mechanism of retinoic acid receptor α (RARα) signal change to regulate neurexin 1 (NRXN1) in the visual cortex and participate in the autistic-like behavior in rats with vitamin A deficiency (VAD). The models of vitamin A normal (VAN) and VAD pregnant rats were established, and some VAD maternal and offspring rats were given vitamin A supplement (VAS) in the early postnatal period. Behavioral tests were performed on 20 offspring rats in each group at the age of 6 weeks. The three-chamber test and the open-field test were used to observe social behavior and repetitive stereotyped behavior. High-performance liquid chromatography was used to measure the serum level of retinol in the offspring rats in each group. Electrophysiological experiments were used to measure the long-term potentiation (LTP) level of the visual cortex in the offspring rats. Quantitative real-time PCR and Western blot were used to measure the expression levels of RARα, NRXN1, and N-methyl-D-aspartate receptor 1 (NMDAR1). Chromatin co-immunoprecipitation was used to measure the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene. The offspring rats in the VAD group had autistic-like behaviors such as impaired social interactions and repetitive stereotypical behaviors, and VAS started immediately after birth improved most of the behavioral deficits in offspring rats. The offspring rats in the VAD group had a significantly lower serum level of retinol than those in the VAN and VAS groups (P<0.05). Compared with the offspring rats in the VAN and VAS groups, the offspring rats in the VAD group had significant reductions in the mRNA and protein expression levels of NMDAR1, RARα, and NRXN1 and the LTP level of the visual cortex (P<0.05). The offspring rats in the VAD group had a significant reduction in the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene in the visual cortex compared with those in the VAN and VAS groups (P<0.05). RARα affects the synaptic plasticity of the visual cortex in VAD rats by regulating NRXN1, thereby participating in the formation of autistic-like behaviors in VAD rats.

Influence of Vitamin A deficiency on the transcriptomic profile of rat meibomian glands.

Vitamin A deficiency (VAD) is associated with chalazion in young children. However, the underlying molecular mechanism remains unclear. In the present study, transcriptome data from rat meibomian glands (MGs) were analyzed to reveal specific molecular responses to VAD. Total RNA was extracted and purified for library preparation and transcriptome sequencing. Differentially expressed genes (DEGs) between vitamin A normal (VAN) and VAD rats were analyzed using DESeq software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using the GO seq R package and KOBAS software. Real-time quantitative reverse transcription polymerase chain reaction was used to validate the RNA sequencing results. The number of DEGs in the VAD group compared to the VAN group was 3129 (1531 upregulated and 1598 downregulated) in the rat MGs. VAD upregulated a large number of lipid metabolism-related genes. GO analysis showed that the most enriched and meaningful terms were related to lipid metabolism (e.g., "oxidation-reduction process, GO: 0,055,114," "lipid metabolic process, GO: 000,662"). KEGG pathway analysis showed that most of the enriched signaling pathways were involved in lipid metabolism, including the PPAR signaling pathway associated with retinoic acid (RA)-mediated nuclear receptors. These findings demonstrate that VAD regulates the expression of numerous genes in the rat MG and that many of these genes are involved in lipid metabolic pathways.

Vitamin A Deficiency in the Early-Life Periods Alters a Diversity of the Colonic Mucosal Microbiota in Rats.

Vitamin A deficiency (VAD) remains a public health issue worldwide, affecting pregnant women and children. The early-life microbiota is a potentially effective intervention target for modulating immune and metabolic development of the host. This paper investigates the effects of VAD during different life periods on the structure of the colonic mucosa microbiota in adolescent rats. The results showed that the concentrations of serum retinol were > ~1.05 μmol/L in maternal VA normal (VAN)rats and < 0.7 μmol/L in maternal VAD rats, while the serum retinol levels were higher than 0.7 μmol/L in the pups of the VAN group and below 0.5 μmol/L in the pups of the VAD group. Compared to the offspring persistent with VAN from embryonic stage (group A), all the remaining groups exhibited an increased ratio of Firmicutes/Bacteroidetes abundance. A metagenome analysis (LEfSe) and a differentially abundant features approach using Metastats for genus abundances revealed that Diaphorobacter and Psychrobacter were increased in the offspring persistent with VAD from embryonic stage (group B);Bifidobacterium was decreased and Staphylococcus was increased in the offspring with VAD after weaning (group C); Propionibacterium and Enterobacter were increased significantly in the offspring with VAD during gestation(group E); and Ochrobactrum was increased in group B and the offspring with VAD during gestation and lactation(group D). Faecalibacterium abundance was significantly and positively related to serum retinol levels, while that of Staphylococcus was significantly and negatively correlated with serum retinol levels. VAD in different life periods can alter the gut microbiome in rats, but VAD in the early-life periods (especially gestation and/or lactation) leads to a diversity of the colonic mucosal microbiota in adolescent rats as well as an imbalance of the ratio between Firmicutes and Bacteroidetes. The early-life period may become a time window of VA intervention to improve intestinal microbiota caused by VA deficiency, but the specific mechanism requires more in-depth research.

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid(RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RAusing the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11β-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11β-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VADrats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11β-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11β-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11β-HSD1.

Melatonin protected against the detrimental effects of microRNA‐363 in a rat model of vitamin A‐associated congenital spinal deformities: Involvement of Notch signaling

Congenital spinal deformities are a result of defective somitogenesis and are associated with vitamin A deficiency (VAD). However, the molecular mechanisms of VAD-associated congenital spinal deformities remain largely unknown. Increasing number of studies suggested that microRNAs and melatonin played important roles in the development of congenital spinal deformities. In this study, we showed that the whole-embryo expression of miR-363 was upregulated in VAD rats. Furthermore, we demonstrated that miR-363 inhibited the proliferation and neuronal differentiation of primary cultured NSCs, accompanied by downregulation of Notch1. To this end, melatonin suppressed miR-363 expression and rescued the effects of miR-363 on NSC proliferation and neuronal differentiation together with restoration of Notch signaling. The present study provided new insights into the mechanism of VAD-associated spinal deformities and the therapeutic effect of melatonin that may lead to novel understanding of the molecular mechanisms of congenital spinal deformities.

Retinoic Acid Facilitates Toll-Like Receptor 4 Expression to Improve Intestinal Barrier Function through Retinoic Acid Receptor Beta

Background/Aims: Vitamin A (VA) protects the intestinal epithelial barrier by improving cell migration and proliferation. Our previous studies demonstrated that VA deficiency (VAD) during pregnancy suppresses the systemic and mucosal immune responses in the intestines of offspring and that VA supplementation (VAS) during early life can increase immune cell counts. However, little is known about the mechanisms by which VA regulates intestinal epithelial barrier function. Methods: Caco-2 cells were treated with all-trans retinoic acid (ATRA) for 24 hours to determine the optimum ATRA concentration to which the cells in question respond. Caco-2 cells were infected with recombinant adenoviruses carrying retinoic acid receptor beta (Ad-RARβ) and small interfering RARβ(siRARβ) to assess the effects of RARβ signalling on the expression of specific proteins. A siTLR4 lentivirus was used to knockdown Toll-like receptor 4 (TLR4) in Caco-2 cells to determine its role in the protective effects of VA on the intestinal epithelial barrier, and experiments involving TLR4-knock-out mice were performed to verify the effect of TLR4. VA normal (VAN), VAD and VAS rat models were established to confirm that changes in RARβ, TLR4 and ZO-2 expression levels that occurred following decreases or increases in retinol concentrations in vivo, and the permeability of the Caco-2 cell monolayer, as well as that of the epithelial barrier of the rat intestine was detected by measuring transepithelial resistance (TER) or performing enzyme-linked immunosorbent assay (ELISA). Retinoic acid receptor (RAR), toll like receptor (TLR) and tight junction (TJ) mRNA and protein expression levels in Caco-2 cells and the colon monolayers in the rat and mouse models were measured by PCR and western blotting, respectively. Co-immunoprecipitation (co-IP) and immunofluorescence staining were performed to assess the interactions among RARβ, TLR4 and zonula occluden-2 (ZO-2) in Caco-2 cells, and chromatin immunoprecipitation (ChIP) assay was performed to assess the binding between RARβ and the TLR4 promoter sequence in Caco-2 cells. Results: In the present study, ATRA treatment not only increased the TER of the Caco-2 monolayer but also up-regulated the expression levels of RARβ, TLR4 and ZO-2 in Caco-2 cells. The expression levels of these three proteins were significantly decreased in the colonic epithelial monolayers of VAD rats compared with those of VAN rats and were significantly increased following VAS in the corresponding group compared with the control group. Furthermore, the above changes in TLR4 and ZO-2 expression levels were augmented or attenuated by Ad-RARβ or siRARβ infection, respectively, in Caco-2 cells. Interestingly, siTLR4 down-regulated ZO-2 expression but did not affect RARβ expression in Caco-2 cells, and in VAD mice the lack of TLR4 did not affect ZO-2 expression. We noted direct interactions between RARβ and TLR4, TLR4 and ZO-2 in Caco-2 cells, and ChIP assay showed that RARβ could bind to the TLR4 promoter but not the ZO-2 promoter in Caco-2 cells. Conclusion: Taken together, our results indicate that RARβ enhanced ZO-2 expression by regulating TLR4 to improve intestinal epithelial barrier function in Caco-2 cells, as well as in rat and mouse models, but not in humans.

Oscillatory potentials in electroretinogram as an early marker of visual abnormalities in vitamin A deficiency.

Vitamin A deficiency (VAD) caused by malnutrition and certain intestinal diseases induces visual impairments, including night blindness and photoreceptor cell dysfunction as indicated by reduced a‑ and b‑waves in an electroretinogram (ERG). The effects of VAD on the inner retinal layer cells, including amacrine and ganglion cells, remain to be elucidated. The functions of these cells are reflected in oscillatory potentials (OPs), another component of the ERG. The present study investigated inner retinal layer cell function in VAD rats by analyzing OPs. In the present study, VAD was induced by feeding Brown Norway rats a vitamin A deficient diet for 10 weeks. A reduced body weight and peri‑papillary opacification indicative of papilledema without histopathological alterations were observed, which are considered early symptoms of VAD. At this stage, the ERG revealed reduced OPs as well as a‑ and b‑waves at various intensities of light stimulation. Further analysis indicated that the ratio of the alterations in OPs was more significant than those of a‑ and b‑waves. After 5 weeks of recovery, these changes returned to control levels. These results suggest that OPs are the most sensitive and early marker of VAD‑associated visual impairment in the ERG.

Vitamin A deficiency impairs spatial learning and memory: the mechanism of abnormal CBP-dependent histone acetylation regulated by retinoic acid receptor alpha.

Vitamin A (VA) is an essential micronutrient. Numerous studies have confirmed that VA deficiency (VAD) leads to a decline in learning and memory function. Our previous studies have demonstrated that retinoic acid nuclear receptor α (RARα) in the hippocampus plays a crucial role in learning and memory, but the exact mechanism for this process is unclear. Epigenetic modifications, particularly histone acetylation, are involved in nervous system development, learning and memory function, and the pathogenesis of neurodegenerative diseases. Histone acetyltransferases (HATs), such as CREB-binding protein (CBP), E1A-binding protein p300 (p300), and p300/CBP-associated factor (PCAF), are critical for regulating memory function. The current study uses RARα and CBP as examples to study the connections between the RA signaling pathway and histone acetylation modification and to reveal the epigenetic mechanism in VAD-induced learning and memory impairment. This study examined the expression of RARα, HATs, acetylated histone H3/H4, and memory-related genes (Zif268, cFos, FosB), as well as the interaction of RARα and CBP in the hippocampus of 8-week-old rats. Additionally, the changes shown in vivo were further assessed in primary cultured neurons with the inhibition or overexpression of RARα. We found significantly lower levels of histone acetylation in the VAD rats. Furthermore, this downregulation, which impairs learning and memory, is induced by the dysregulation of CBP-dependent histone acetylation that is mediated by RARα. This work provides a solid theoretical foundation and experimental basis for the importance of ensuring sufficient nutritional VA during pregnancy and early life to prevent impairments of learning and memory in adulthood.

Vitamin A status regulates glucocorticoid availability in Wistar rats: consequences on cognitive functions and hippocampal neurogenesis?

A disruption of the vitamin A signaling pathway has been involved in age-related memory decline and hippocampal plasticity alterations. Using vitamin A deficiency (VAD), a nutritional model leading to a hyposignaling of the retinoid pathway, we have recently demonstrated that retinoic acid (RA), the active metabolite of vitamin A, is efficient to reverse VAD-induced spatial memory deficits and adult hippocampal neurogenesis alterations. Besides, excess of glucocorticoids (GCs) occurring with aging is known to strongly inhibit hippocampal plasticity and functions and few studies report on the counteracting effects of RA signaling pathway on GCs action. Here, we have addressed whether the modulation of brain GCs availability could be one of the biological mechanisms involved in the effects of vitamin A status on hippocampal plasticity and functions. Thus, we have studied the effects of a vitamin A-free diet for 14 weeks and a 4-week vitamin A supplementation on plasma and hippocampal corticosterone (CORT) levels in Wistar rats. We have also investigated corticosteroid binding globulin (CBG) binding capacity and 11beta-Hydrosteroid Dehydrogenase type 1 (11β-HSD1) activity, both important modulators of CORT availability at the peripheral and hippocampal levels respectively. Interestingly, we show that the vitamin A status regulates levels of free plasma CORT and hippocampal CORT levels, by acting through a regulation of CBG binding capacity and 11β-HSD1 activity. Moreover, our results suggest that increased CORT levels in VAD rats could have some deleterious consequences on spatial memory, anxiety-like behavior and adult hippocampal neurogenesis whereas these effects could be corrected by a vitamin A supplementation. Thus, the modulation of GCs availability by vitamin A status is an important biological mechanism that should be taken into account in order to prevent age-related cognitive decline and hippocampal plasticity alterations.

Vitamin A deficiency impairs postnatal cognitive function via inhibition of neuronal calcium excitability in hippocampus

Vitamin A (VA) is important for postnatal brain development, and VA deficiency (VAD) can cause learning and spatial memory deficits in rats. Most of the biological functions of VA are mediated by retinoic acid (RA). To investigate the mechanisms underlying VA deficits, mother rats were fed elemental diets to achieve blood VA levels classified as normal, deficient or severely deficient. Shuttle box and Morris water maze tests revealed impairments in learning ability and spatial memory, respectively, in adolescent VAD rats (p 30-35). Electrophysiology showed weaker long-term potentiation in VAD rats compared to VA normal rats. Examination of NMDA-induced calcium (Ca(2+) ) excitability revealed decreased excitability in hippocampal slices from VAD rats during postnatal development. Relative to VA normal rats, VAD rats also had decreased NMDA receptor NR1 mRNA and protein expression in later stages of postnatal development (p 10-30), as well as differences in retinoic acid receptor (RARα) mRNA and protein expression. Furthermore, primary hippocampal neurons in culture showed increased neuronal Ca(2+) excitability in response to all-trans-RA or 9-cis-RA, coupled with increases in RARα and NR1 expression similar to those observed in vivo. We also found weaker calcium excitability and lower expression of NR1 mRNA and protein after specific silencing of RARα. Finally, we found that RA signals affected the expression of NR1 do not directly through transcriptional regulation. These data support the new idea that continuous postnatal VAD inhibits RARα expression, which decreases NR1 expression via no direct transcriptional regulation and then inhibits hippocampal neuronal Ca(2+) excitability which affects long-term potentiation, finally producing deficits in active learning and spatial memory in adolescence.

Restoration of bone morphology by retinoic acid in a Vitamin A deficiency model in rats

These studies measured the effect of vitamin A deficiency (VAD) on bone structure and reabsorption as influenced by retinoic acid or cod liver oil in a rat model. Weanling rats received a vitamin A sufficient diet (controls) or a VAD diet for 9 weeks. From week ten to thirteen the VAD group split into 4 treatment groups: continued VAD, control, supplemented with retinoic acid or with cod liver oil containing vitamins A and D. At necropsy, femurs, liver, lungs and kidneys were formalin fixed and stained for histology. Bone osteoblast counts and histopathology scoring were performed. Femur thicknesses (400×, 3 sections/bone) were recorded as internal/external diameter ratios. Femurs of VAD rats had thinner cortical bone than controls (p&lt;0.03). Addition to the VAD diet of retinoic acid, but not of cod liver oil restored the femurs to normal thickness. VAD rats had decreased numbers of both endosteal and periosteal osteoblasts vs controls (p&lt;0.05) which were increased significantly by retinoic acid (p&lt;0.002). Osteoclasts were not detected. VAD diet produced lung inflammation and emphysema and increased fat in the liver. Treatment with retinoic acid or cod liver oil restored pulmonary morphology but only retinoic acid restored the liver. Kidneys were normal. Retinoic acid therefore was the most effective in reversing VAD effects.

Vitamin A deficiency results in dysregulation of lipid efflux pathway in rat kidney

The mechanisms of action of vitamin A deficiency (VAD) on lipid metabolism in the rat kidney were investigated in adult female rats and their offspring. The rats were randomized into three groups: (1) control, in which the mother and offspring received a normal diet (4000 retinol IU/kg diet) for 8 weeks; (2) VAD group, in which the mothers and offspring received a VAD diet (400 retinol IU/kg diet) for 8 weeks; (3) vitamin A-refed group, in which a group of pups on a VAD diet for 8 weeks received a complete diet (6500 retinol IU/kg diet) for 15 days. The lipid metabolism of the offsprings' kidneys and its relation to the expression of apolipoprotein B100 (Apo-B100), liver X receptor alpha (LXRalpha), and retinoid X receptor-alpha/beta (RXRalpha/beta) mRNA was analyzed. VAD was found to alter renal lipid metabolism and its immune environment due to the expression of Apo-B100. Compared with the control, VAD rats had significantly higher levels of transforming growth factor-beta 1 and lower levels of ABCA1, a key gene involved in cholesterol efflux and tissue lipid homeostasis. The expression of LXRalpha and RXRalpha/beta mRNA also decreased in the VAD rat kidney. Vitamin A refeeding reversed all of the changes. Lipid metabolism involved in renal reverse cholesterol transport may be mediated by decreasing the signaling through the ABCA1 cholesterol efflux pathway, which is significantly modified in kidneys of vitamin A-deficient rats.

Expression of retinoic acid receptors in intestinal mucosa and the effect of vitamin A on mucosal immunity

Objective To explore the mechanism of vitamin A (VA) modulation of mucosal immunity, the expression of retinoic acid receptors in intestinal mucosa was measured, and the effect of VA on intestinal dendritic cells (DCs) and mucosal cytokine production was examined. Methods The expression of retinoic acid receptor (RAR-α, RAR-β, RAR-γ, RXR-α, RXR-β, RXR-γ) mRNA, the distribution and number of DCs, and the protein secretion of interleukin (IL)-12, T-helper type 1/2 cells (interferon [IFN]-γ/IL-4), and regulatory (IL-10) cytokines in the mucosa of terminal ileum in normal rats and rats with VA deficiency (VAD) were detected by reverse transcriptase polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. The effect of all-trans retinoic acid on the number and maturation of DCs and the gene expression of RAR-α and cytokines listed earlier in cultured Peyer's patches were examined by flow cytometry and reverse transcriptase polymerase chain reaction, respectively. Results In the intestinal mucosa of VAD rats, RAR-α mRNA was downregulated, DC number increased, the protein secretion of IL-12 was increased, but the secretion of IFN-γ and IL-10 decreased. In in vitro cultured Peyer's patches, all-trans retinoic acid promoted DC maturation, upregulated RAR-α mRNA, reduced IL-12 and IFN-γ, but increased IL-10 gene expression; these effects of all-trans retinoic acid were reversed when cultured with Ro 41-5253 (a specific antagonist of RAR-α). Conclusion Vitamin A may be potent in reducing intestinal inflammation and restoring impaired antibody responses in a VAD situation. The effect of VA on DCs could be an important mechanism contributing to altered mucosal immunity. RAR-α may mostly play a role in the action of VA.

Vitamin A deficiency increases airway resistance following C-fiber stimulation

Vitamin A deficiency (VAD) remains an important problem in the developing world where environmental air pollution is increasing. Because the coincidence of these factors could increase the prevalence of asthma in these regions, airway reactivity to methacholine (MCh), capsaicin, and sulfur dioxide was studied in VAD rats. The impedance to a small volume oscillation was analyzed to determine airway resistance (R(aw)) and lung elastance (H). VAD rats demonstrated larger increases in R(aw) and H after the administration of methacholine, and in R(aw) after administration of capsaicin or sulfur dioxide. The muscarinic receptor-2 (M2R) selective antagonist AFDX-116 enhanced the effect of capsaicin in vitamin A sufficient (VAS) but not VAD rats and retinoic acid-administration partially restored this enhancement. These data indicate that diminished auto-inhibitory muscarinic receptor-2 function contributed to this increased airway responsiveness to pulmonary C-fiber stimulation in VAD rats. If children with VAD also have diminished M2R function, they may be more prone to develop asthma, particularly in the presence of environmental co-factors such as sulfur dioxide.

Vitamin A deficiency alters pulmonary parenchymal collagen and tissue mechanics

The mechanical properties of the pulmonary parenchyma are strongly influenced by the collagen and elastic fibers that course through the alveolar interstitium and interconnect the bronchovascular bundles. Vitamin A deficiency (VAD) produces effacement and remodeling of the alveolar architecture, resulting in alternating areas of alveolar dilatation and collapse. To better understand the mechanical consequences and reversibility of this remodeling process, we have examined how the remodeling of collagen and elastic fibers correlates with the mechanical properties of the lung parenchyma in VAD rats. An oscillatory impulse was applied at different levels of stress on the fiber network and the tissue damping (G), elastance (H), hysteresivity (G/H, eta) were analyzed. At a supra-physiological functional residual capacity, the lung parenchyma of VAD rats exhibited a lower G and H than Vitamin A sufficient (VAS) rats, which was accompanied by a significant decrease in the quantity of parenchymal collagen and collagen fibers. Retinoic acid (RA) administration restored the parenchymal collagen and mechanical properties.

The Administration of Retinoic Acid Down-Regulates cAMP-Responsive Element Modulator (CREM) mRNA in Vitamin A-Deficient Testes

Studies using genetics and vitamin A deficiency (VAD) have shown that vitamin A and retinoids play essential roles in spermatogenesis at the pre-meiotic stage. To understand the mechanisms of control in spermatogenesis by retinoic acid, we investigated whether retinoic acids regulate the expression of downstream transcription factors that are essential for spermatogenesis. In this study, we found that administration of all-trans retinoic acid (ATRA) or retinol to VAD rats down-regulates the testicular mRNA levels of the cAMP responsive element modulator (CREM), an essential transcription factor for spermatogenesis. Conversely, depletion of retinoids from the diet leds to an up-regulation of CREM expression in adult testes. In addition, RT-PCR analysis indicated that ATRA specifically represses the expression of the activator spliced variant of CREM (CREMtau). These results suggest that retinoids function as a negative regulator of CREM expression in testes.

Vitamin A deficiency promotes bronchial hyperreactivity in rats by altering muscarinic M(2) receptor function.

Vitamin A deficiency (VAD) remains an important health problem among children in developing countries. Children living in these areas have a higher mortality from respiratory infections, which likely results in part from suboptimal nutrition, including VAD. Bronchial hyperreactivity can follow viral respiratory infections and may complicate the recovery. To investigate whether VAD promotes bronchial hyperreactivity, we have assessed methacholine-induced bronchoconstriction in VAD and vitamin A-sufficient rats. Bronchial constriction developed at lower concentrations of inhaled methacholine in VAD than in vitamin A-sufficient rats. This did not result from an increase in the bronchial wall thickness or the clearance of a small molecule (with a size similar to methacholine) from the air space. The function and abundance of the muscarinic M(2) receptors in bronchial tissue were reduced in VAD rats, suggesting that this receptor may contribute to these animals' diminished ability to limit cholinergic-mediated bronchoconstriction. A similar reduction in muscarinic M(2) receptor function has been observed in asthma. Vitamin A (retinol) and its congeners (retinoids) may be required to regulate bronchial responsiveness in addition to maintaining a normal bronchial epithelium.

Retinol-induced stage synchronization in seminiferous tubules of the rat.

Vitamin A deficiency (VAD) in rats causes a progressive germ cell depletion and cessation of spermatogenesis resulting in seminiferous tubules which contain only Sertoli cells, spermatogonia and a small number of preleptotene spermatocytes. Spermatogenesis can be rapidly restored by the administration of retinol. Our preliminary studies suggested a partial stage synchronization of many seminiferous tubules in VAD male rats subsequently treated with retinol. To confirm this observation and to achieve a better synchronization, VAD rats received 2 SC injections of retinol suspended in sesame oil followed by daily oral administrations of 0.5 mg of retinol. In all rats an almost perfect synchronous stage development of seminiferous tubules evolved in a predictable manner and was maintained through 2 spermiations.