Ndfip2 is a potential regulator of the iron transporter DMT1 in the liver

Foot, Natalie; Gembus, Kelly M.; Mackenzie, Kimberly D.; Kumar, Sharad

doi:10.1038/srep24045

Cited by 16 publications

(9 citation statements)

References 35 publications

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“…The sexual dimorphism in Cd accumulation may be related to the expression of DMT1, the non-specific divalent metal transporter, which mediates the absorption of Cd in the small intestine 43,44 . The density of DMT1 transporters increases in females under conditions of Fe depletion (see below) and pregnancy 45–47 .…”

Section: Discussionmentioning

confidence: 98%

Cadmium and High-Fat Diet Disrupt Renal, Cardiac and Hepatic Essential Metals

Young

Yan

et al. 2019

Sci Rep

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Exposure to the environmental toxicant cadmium (Cd) contributes to the development of obesity-associated diseases. Obesity is a risk factor for a spectrum of unhealthy conditions including systemic metabolic dyshomeostasis. In the present study, the effects of whole-life exposure to environmentally-relevant concentrations of Cd on systemic essential metal distribution in adult mice fed a high-fat diet (HFD) were examined. For these studies, male and female mice were exposed to Cd-containing drinking water for >2 weeks before breeding. Pregnant mice and dams with offspring were exposed to Cd-containing drinking water. After weaning, offspring were continuously exposed to the same Cd concentration as their parents, and divided into HFD and normal (low) fat diet (LFD) groups. At 10 and 24 weeks, mice were sacrificed and blood, liver, kidney and heart harvested for metal analyses. There were significant concentration dependent increases in Cd levels in offspring with kidney > liver > heart. Sex significantly affected Cd levels in kidney and liver, with female animals accumulating more metal than males. Mice fed the HFD showed > 2-fold increase in Cd levels in the three organs compared to similarly treated LFD mice. Cadmium significantly affected essential metals levels in blood, kidney and liver. Additionally, HFD affected essential metal levels in these three organs. These findings suggest that Cd interacts with HFD to affect essential metal homeostasis, a phenomenon that may contribute to the underlying mechanism responsible for the development of obesity-associated pathologies.

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Section: Discussionmentioning

confidence: 98%

Cadmium and High-Fat Diet Disrupt Renal, Cardiac and Hepatic Essential Metals

Young

Yan

et al. 2019

Sci Rep

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“…Total RNA was isolated from kidneys using TRIzol Reagent (Thermo Fisher Scientific) and RNA was reverse-transcribed with a High Capacity cDNA Reverse Transcription Kit (Applied Biosciences, Foster city, CA, USA). qRT-PCR was performed and analyzed as described, 35 where all data are normalized to tbp (TATA box-binding protein) levels. Primer sequences are detailed in Supplementary Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Deletion of Nedd4-2 results in progressive kidney disease in mice

et al. 2017

Self Cite

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NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na+ channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na+Cl− cotransporter expression, increased Na+ reabsorption, hypertension and markedly reduced levels of aldosterone. The observed nephropathy is characterized by fibrosis, tubule epithelial cell apoptosis, dilated/cystic tubules, elevated expression of kidney injury markers and immune cell infiltration, characteristics reminiscent of human chronic kidney disease. Importantly, we demonstrate that the extent of kidney injury can be partially therapeutically ameliorated in mice with nephron-specific deletions of Nedd4-2 by blocking ENaC with amiloride. These results suggest that increased Na+ reabsorption via ENaC causes kidney injury and establish a novel role of NEDD4-2 in preventing Na+-induced nephropathy. Contrary to some recent reports, our data also indicate that ENaC is the primary in vivo target of NEDD4-2 and that Nedd4-2 deletion is associated with hypertension on a normal Na+ diet. These findings provide further insight into the critical function of NEDD4-2 in renal pathophysiology.

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“…1). Of these genes, three are involved in metal ion transport (Solute Carrier Family 30 Member 10 [SLC30A10], Nedd4 Family Interacting Protein 2 [NDFIP2], and Family With Sequence Similarity 21 Member C [FAM21]) (Ohana et al, 2006; Yang et al, 2012; Shusterman et al, 2014; Gallon & Cullen, 2015; Lee, Chang & Blackstone, 2016; Foot et al, 2016), while three others have ontology terms associated with immune response (Signal Peptide Peptidase Like 2A [SPPL2A: Biological Process-regulation of immune response], Ataxin 2 [ATXN2: Biological Process - negative regulation of multicellular organism growth], SET Domain Containing 6 [SETD6: Biological Process-regulation of inflammatory response]). Given the roles that the spleen and liver play in immunological processes and the genes identified to be under positive selection in these tissues, it is possible that both the spleen and liver of the tuco-tuco are particularly involved in adaptation to the subterranean environment.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic analyses reveal tissue-specific selection on genes related to apoptotic processes in the subterranean rodent,Ctenomys sociabilis

Lang

Kordonowy

Lacey³

et al. 2018

Preprint

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Specialization for a subterranean existence is expected to impact multiple aspects of an organism’s biology, including behavior, physiology, and genomic structure. While the phenotypic correlates of life underground have been extensively characterized, the genetic bases for these traits are not well understood, due in part to the challenges of generating large, multi-locus data sets using traditional DNA sequencing strategies. To begin exploring the genomic architecture of adaptation to a subterranean existence, we generated high-quality de novo transcriptome assemblies for 8 different tissue types (hippocampus, hypothalamus, kidney, liver, spleen, ovary, testis, skin) obtained from the colonial tuco-tuco (Ctenomys sociabilis), a group-living species of subterranean rodent that is endemic to southwestern Argentina. From these transcriptomes, we identified genes that are evolving more rapidly in the C. sociabilis lineage compared to other subterranean species of rodents. These comparisons suggest that genes associated with immune response, cell-cycle regulation, and heavy metal detoxification have been subject to positive selection in C. sociabilis. Comparisons of transcripts from different tissues suggest that the spleen and liver - organs involved in immune function and detoxification - may be particularly important sites for these adaptations, thereby underscoring the importance of including multiple tissue types in analyses of transcriptomic variation. In addition to providing an important resource for future genomic studies of C. sociabilis, our analyses generate new insights into the genomic architecture of functionally significant phenotypic traits in free-living mammals.

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Ndfip2 is a potential regulator of the iron transporter DMT1 in the liver

Cited by 16 publications

References 35 publications

Cadmium and High-Fat Diet Disrupt Renal, Cardiac and Hepatic Essential Metals

Cadmium and High-Fat Diet Disrupt Renal, Cardiac and Hepatic Essential Metals

Deletion of Nedd4-2 results in progressive kidney disease in mice

Transcriptomic analyses reveal tissue-specific selection on genes related to apoptotic processes in the subterranean rodent,Ctenomys sociabilis

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