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  • 1
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    Lithium induces aerobic glycolysis and glutaminolysis in collecting duct principal cells
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Renal Physiology Vol. 314, No. 2 ( 2018-02-01), p. F230-F239
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 314, No. 2 ( 2018-02-01), p. F230-F239
    Abstract: Lithium, given to bipolar disorder patients, causes nephrogenic diabetes insipidus (Li-NDI), a urinary-concentrating defect. Li-NDI occurs due to downregulation of principal cell AQP2 expression, which coincides with principal cell proliferation. The metabolic effect of lithium on principal cells, however, is unknown and investigated here. In earlier studies, we showed that the carbonic anhydrase (CA) inhibitor acetazolamide attenuated Li-induced downregulation in mouse-collecting duct (mpkCCD) cells. Of the eight CAs present in mpkCCD cells, siRNA and drug treatments showed that downregulation of CA9 and to some extent CA12 attenuated Li-induced AQP2 downregulation. Moreover, lithium induced cell proliferation and increased the secretion of lactate. Lithium also increased urinary lactate levels in wild-type mice that developed Li-NDI but not in lithium-treated mice lacking ENaC, the principal cell entry site for lithium. Inhibition of aerobic glycolysis with 2-deoxyglucose (2DG) attenuated lithium-induced AQP2 downregulation in mpkCCD cells but did not attenuate Li-NDI in mice. Interestingly, NMR analysis demonstrated that lithium also increased the urinary succinate, fumarate, citrate, and NH 4 + levels, which were, in contrast to lactate, not decreased by 2DG. Together, our data reveal that lithium induces aerobic glycolysis and glutaminolysis in principal cells and that inhibition of aerobic glycolysis, but not the glutaminolysis, does not attenuate Li-NDI.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00297.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
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  • 2
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    Genetic variation associates with susceptibility for cigarette smoke-induced neutrophilia in mice
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 308, No. 7 ( 2015-04-01), p. L693-L709
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 308, No. 7 ( 2015-04-01), p. L693-L709
    Abstract: Neutrophilic airway inflammation is one of the major hallmarks of chronic obstructive pulmonary disease and is also seen in steroid resistant asthma. Neutrophilic airway inflammation can be induced by different stimuli including cigarette smoke (CS). Short-term exposure to CS induces neutrophilic airway inflammation in both mice and humans. Since not all individuals develop extensive neutrophilic airway inflammation upon smoking, we hypothesized that this CS-induced innate inflammation has a genetic component. This hypothesis was addressed by exposing 30 different inbred mouse strains to CS or control air for 5 consecutive days, followed by analysis of neutrophilic lung inflammation. By genomewide haplotype association mapping, we identified four susceptibility genes with a significant association to lung tissue levels of the neutrophil marker myeloperoxidase under basal conditions and an additional five genes specifically associated with CS-induced tissue MPO levels. Analysis of the expression levels of the susceptibility genes by quantitative RT-PCR revealed that three of the four genes associated with CS-induced tissue MPO levels had CS-induced changes in gene expression levels that correlate with CS-induced airway inflammation. Most notably, CS exposure induces an increased expression of the coiled-coil domain containing gene, Ccdc93, in mouse strains susceptible for CS-induced airway inflammation whereas Ccdc93 expression was decreased upon CS exposure in nonsusceptible mouse strains. In conclusion, this study shows that CS-induced neutrophilic airway inflammation has a genetic component and that several genes contribute to the susceptibility for this response.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00118.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477300-4
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  • 3
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    Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects
    American Physiological Society ; 2008
    In:  Physiological Genomics Vol. 35, No. 3 ( 2008-11), p. 296-304
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 35, No. 3 ( 2008-11), p. 296-304
    Abstract: The vacuolated lens ( vl) mouse mutant arose spontaneously on the C3H/HeSn background and exhibits neural tube defects (NTDs), congenital cataract, and occasionally a white belly spot. We previously reported that 1) the vl phenotypes are due to a mutation in an orphan G protein-coupled receptor (GPCR), Gpr161; 2) the penetrance of the vl NTD and cataract phenotypes are affected by genetic background, allowing three unlinked quantitative trait loci (QTL) to be mapped (modifiers of vacuolated lens, Modvl1-3); and 3) phenotype-based bioinformatics followed by genetic and molecular analysis identified a lens-specific transcription factor that contributes to the cataract-modifying effect of Modvl3. We now extend this analysis in three ways. First, using the Gpr161 mutation to unequivocally identify mutant adults and embryos, we determined that ∼50% of vl/vl NTD-affected embryos die during development. Second, the MOLF/Ei genetic background suppresses this embryonic lethality but increases the incidence of the adult belly spot phenotype. Additional QTL analysis was performed, and two novel modifiers were mapped [ Modvl4, logarithm of odds ratio (LOD) 4.4; Modvl5, LOD 5.0] . Third, phenotype-based bioinformatics identified candidate genes for these modifiers including two GPCRs that cause NTD or skin/pigmentation defects ( Modvl4: Frizzled homolog 6; Modvl5: Melanocortin 5 receptor). Because GPCRs form oligomeric complexes, these genes were resequenced and nonsynonymous coding variants were identified. Bioinformatics and protein modeling suggest that these variants may be functional. Our studies further establish vl as a multigenic mouse model for NTDs and identify additional QTL that interact with Gpr161 to regulate neurulation.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.90260.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
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  • 4
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    Genetic contributors to lipoprotein cholesterol levels in an intercross of 129S1/SvImJ and RIIIS/J inbred mice
    American Physiological Society ; 2004
    In:  Physiological Genomics Vol. 17, No. 2 ( 2004-04-13), p. 114-121
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 17, No. 2 ( 2004-04-13), p. 114-121
    Abstract: To determine the genetic contribution to variation among lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) analyses on an intercross between mouse strains RIIIS/J and 129S1/SvImJ. Male mice of the parental strains and the reciprocal F 1 and F 2 populations were fed a high-cholesterol, cholic acid-containing diet for 8–12 wk. At the end of the feeding period, plasma total, high-density lipoprotein (HDL), and non-HDL cholesterol were determined. For HDL cholesterol, we identified three significant QTLs on chromosomes (Chrs) 1 ( D1Mit507, 88 cM, 72–105 cM, 4.8 LOD), 9 ( D11Mit149, 14 cM, 10–25 cM, 9.4 LOD), and 12 ( D12Mit60, 20 cM, 0–50 cM, 5.0 LOD). These QTLs were considered identical to QTLs previously named Hdlq5, Hdlq17, and Hdlq18, respectively, in crosses sharing strain 129. For total cholesterol, we identified two significant QTLs on Chrs 1 and 9, which were named Chol10 ( D1Mit507, 88 cM, 10–105 cM, 3.9 LOD) and Chol11 ( D11Mit149, 14 cM, 0–30 cM, 4.4 LOD), respectively. In addition, for total cholesterol, we identified two suggestive QTLs on Chrs 12 (distal) and 17, which remain unnamed. For non-HDL cholesterol, we identified and named one new QTL on Chr 17, Nhdlq3 ( D17Mit221, 58 cM, 45–60 cM, 3.4 LOD). Nhdlq3 colocalized with orthologous human QTLs for lipoprotein phenotypes, and with Abcg5 and Abcg8. Overall, we detected eight QTLs for lipoprotein cholesterol concentrations on Chrs 1, 9, 12, and 17 (each two per chromosome), including a new QTL for non-HDL cholesterol, Nhdlq3, on Chr 17.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00168.2003
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2004
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  • 5
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    Genetic variance is associated with susceptibility for cigarette smoke-induced DAMP release in mice
    American Physiological Society ; 2017
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 313, No. 3 ( 2017-09-01), p. L559-L580
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 313, No. 3 ( 2017-09-01), p. L559-L580
    Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by unresolved neutrophilic airway inflammation and is caused by chronic exposure to toxic gases, such as cigarette smoke (CS), in genetically susceptible individuals. Recent data indicate a role for damage-associated molecular patterns (DAMPs) in COPD. Here, we investigated the genetics of CS-induced DAMP release in 28 inbred mouse strains. Subsequently, in lung tissue from a subset of strains, the expression of the identified candidate genes was analyzed. We tested whether small interfering RNA-dependent knockdown of candidate genes altered the susceptibility of the human A549 cell line to CS-induced cell death and DAMP release. Furthermore, we tested whether these genes were differentially regulated by CS exposure in bronchial brushings obtained from individuals with a family history indicative of either the presence or absence of susceptibility for COPD. We observed that, of the four DAMPs tested, double-stranded DNA (dsDNA) showed the highest correlation with neutrophilic airway inflammation. Genetic analyses identified 11 candidate genes governing either CS-induced or basal dsDNA release in mice. Two candidate genes ( Elac2 and Ppt1) showed differential expression in lung tissue on CS exposure between susceptible and nonsusceptible mouse strains. Knockdown of ELAC2 and PPT1 in A549 cells altered susceptibility to CS extract-induced cell death and DAMP release. In bronchial brushings, CS-induced expression of ENOX1 and ARGHGEF11 was significantly different between individuals susceptible or nonsusceptible for COPD. Our study shows that genetic variance in a mouse model is associated with CS-induced DAMP release, and that this might contribute to susceptibility for COPD.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00466.2016
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2017
    detail.hit.zdb_id: 1477300-4
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  • 6
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    Automatic glomerular identification and quantification of histological phenotypes using image analysis and machine learning
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Renal Physiology Vol. 315, No. 6 ( 2018-12-01), p. F1644-F1651
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 315, No. 6 ( 2018-12-01), p. F1644-F1651
    Abstract: Current methods of scoring histological kidney samples, specifically glomeruli, do not allow for collection of quantitative data in a high-throughput and consistent manner. Neither untrained individuals nor computers are presently capable of identifying glomerular features, so expert pathologists must do the identification and score using a categorical matrix, complicating statistical analysis. Critical information regarding overall health and physiology is encoded in these samples. Rapid comprehensive histological scoring could be used, in combination with other physiological measures, to significantly advance renal research. Therefore, we used machine learning to develop a high-throughput method to automatically identify and collect quantitative data from glomeruli. Our method requires minimal human interaction between steps and provides quantifiable data independent of user bias. The method uses free existing software and is usable without extensive image analysis training. Validation of the classifier and feature scores in mice is highlighted in this work and shows the power of applying this method in murine research. Preliminary results indicate that the method can be applied to data sets from different species after training on relevant data, allowing for fast glomerular identification and quantitative measurements of glomerular features. Validation of the classifier and feature scores are highlighted in this work and show the power of applying this method. The resulting data are free from user bias. Continuous data, such that statistical analysis can be performed, allows for more precise and comprehensive interrogation of samples. These data can then be combined with other physiological data to broaden our overall understanding of renal function.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00629.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
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  • 7
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    Quantitative trait loci that determine lipoprotein cholesterol levels in an intercross of 129S1/SvImJ and CAST/Ei inbred mice
    American Physiological Society ; 2004
    In:  Physiological Genomics Vol. 17, No. 1 ( 2004-03-12), p. 60-68
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 17, No. 1 ( 2004-03-12), p. 60-68
    Abstract: To identify genetic determinants of lipoprotein levels, we are performing quantitative trait locus (QTL) analysis on a series of mouse intercrosses in a “daisy chain” experimental design, to increase the power of detecting QTL and to identify common variants that should segregate in multiple intercrosses. In this study, we intercrossed strains CAST/Ei and 129S1/SvImJ, determined HDL, total, and non-HDL cholesterol levels, and performed QTL mapping using Pseudomarker software. For HDL cholesterol, we identified two significant QTL on chromosome (Chr) 1 ( Hdlq5, 82 cM, 60–100 cM) and Chr 4 ( Hdlq10, 20 cM, 10–30 cM). For total cholesterol, we identified three significant QTL on Chr 1 ( Chol7, 74 cM, 65–80 cM), Chr 4 ( Chol8, 12 cM, 0–30 cM), and Chr 17 ( Chol9, 54 cM, 20–60 cM). For non-HDL cholesterol, we identified significant QTL on Chr 8 ( Nhdlq1, 34 cM, 20–60 cM) and Chr X ( Nhdlq2, 6 cM, 0–18 cM). Hdlq10 was the only QTL detected in two intercrosses involving strain CAST/Ei. Hdlq5, Hdlq10, Nhdlq1, and two suggestive QTL at D7Mit246 and D15Mit115 coincided with orthologous human lipoprotein QTL. Our analysis furthers the knowledge of the genetic control of lipoprotein levels and points to the importance of Hdlq10, which was detected repeatedly in multiple studies.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00142.2003
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2004
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  • 8
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    Genetic analysis of mouse strains with variable serum sodium concentrations identifies the Nalcn sodium channel as a novel player in osmoregulation
    American Physiological Society ; 2011
    In:  Physiological Genomics Vol. 43, No. 5 ( 2011-03), p. 265-270
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 43, No. 5 ( 2011-03), p. 265-270
    Abstract: In central osmoregulation, a 1–2% rise in plasma osmolality is detected by specialized osmoreceptors located in the circumventricular organs of the hypothalamus. A disturbance in this tightly regulated balance will result in either hyponatremia or hypernatremia, which are both common electrolyte disorders in hospitalized patients. Despite the high clinical importance of hypo- and hypernatremia and the fact that this vital process has been studied for many years, the genes and corresponding proteins involved in this process are just beginning to be identified. To identify novel genes involved in the (patho-)physiology of osmoregulation, we therefore employed haplotype association mapping on an aging group of 27 inbred mouse strains. Serum sodium concentrations were determined in all strains at 6, 12, and 18 mo of age, and high-resolution mapping was performed for males and females separately. We identified a total of five loci associated with the serum sodium concentration of which the locus on chromosome 14, containing only one known gene ( Nalcn), showed the strongest correlation. Within this locus three different haplotypes could be distinguished, which associated with different average serum sodium levels. The association of Nalcn with sodium levels was confirmed by analysis of heterozygous Nalcn knockout mice, which displayed hypernatremia compared with wild-type littermates. Our study demonstrates that Nalcn associates with serum sodium concentrations in mice and indicates that Nalcn is an important novel player in osmoregulation.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00188.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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  • 9
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    Quantitative trait locus mapping of genes that regulate HDL cholesterol in SM/J and NZB/B1NJ inbred mice
    American Physiological Society ; 2002
    In:  Physiological Genomics Vol. 9, No. 2 ( 2002-05-10), p. 93-102
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 9, No. 2 ( 2002-05-10), p. 93-102
    Abstract: To investigate the quantitative trait loci (QTL) regulating plasma cholesterol, the female progeny of an (SM×NZB/ B1NJ)×NZB/B1NJ backcross were fed an atherogenic diet. After 18 wk, plasma total cholesterol and high-density lipoprotein cholesterol (HDL-C) was measured. HDL-C concentrations were greater in NZB than in SM mice. For standard chow-fed mice, QTL were found near D5Mit370 and D18Mit34. For mice fed an atherogenic diet, a QTL was found near D5Mit239. The QTL for chow-fed and atherogenic-fed mice on chromosome 5 seem to be two different loci. We used a multitrait analysis to rule out pleiotropy in favor of a two-QTL hypothesis. Furthermore, the HDL-C in these strains was induced by the high-fat diet. For inducible HDL-C, one significant locus was found near D15Mit39. The gene for an HDL receptor, Srb1, maps close to the HDL-C QTL at D5Mit370, but the concentrations of Srb1 mRNA and SR-B1 protein and the gene sequence of NZB/B1NJ and SM/J did not support Srb1 as a candidate gene. With these QTL, we have identified chromosomal regions that affect lipoprotein profiles in these strains.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00107.2001
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2002
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  • 10
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    FAR2 is associated with kidney disease in mice and humans
    American Physiological Society ; 2018
    In:  Physiological Genomics Vol. 50, No. 8 ( 2018-08-01), p. 543-552
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 50, No. 8 ( 2018-08-01), p. 543-552
    Abstract: Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. Taken together, these results highlight FAR2’s role in the development of mesangial matrix expansion and chronic kidney disease.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00118.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
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