The pressure of finding human hypertension genes : New tools, old dilemmas
- Charchar, Fadi, Zimmerli, Lukas, Tomaszewski, Maciej
- Authors: Charchar, Fadi , Zimmerli, Lukas , Tomaszewski, Maciej
- Date: 2008
- Type: Text , Journal article
- Relation: Journal of Human Hypertension Vol. 22, no. (2008), p. 821–828
- Full Text: false
- Reviewed:
- Description: Researchers in hypertension genetics feel like they are left behind again. It always seems that the 'other' complex diseases are ahead in the race. Evolving new technologies in the form of genome-wide arrays and 'omics' technologies mean that investigators can now potentially identify many novel disease factors in one large-scale experiment. Hypertension research now faces the challenge of where to go next after the first genome-wide association experiments failed to provide robust candidates. In this review, we contemplate the old dilemma of whether such genes may ever be found; however, we believe advancing technologies and plummeting costs of large-scale experiments will contribute to the identification of novel molecules that underlie essential hypertension.
- Tomaszewski, Maciej, Charchar, Fadi, Maric, Christine, Kuzniewicz, Roman, Gola, Mateusz, Grzeszczak, Wladyslaw, Samani, Nilesh, Zukowska-Szczechowska, Ewa
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Maric, Christine , Kuzniewicz, Roman , Gola, Mateusz , Grzeszczak, Wladyslaw , Samani, Nilesh , Zukowska-Szczechowska, Ewa
- Date: 2009
- Type: Text , Journal article
- Relation: American Journal of Hypertension Vol. 22, no. 1 (2009), p. 100-105
- Full Text: false
- Reviewed:
- Description: Background: Men exhibit higher risk of nondiabetic renal diseases than women. This male susceptibility to renal disease may be mediated by gender-specific factors such as sex hormones. Methods: We have undertaken a cross-sectional examination of associations between renal function (creatinine clearance estimated based on Cockcroft-Gault equation) and circulating levels of sex steroids (total testosterone, total estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), and dihydrotestosterone) in 928 young (mean age: 18.5 ± 1.2 years) men. Results: Both androstenedione and DHEA-S showed inverse linear associations with renal function in the crude analysis of lean men (those with body mass index (BMI) less than median). However, only DHEA-S retained its association with renal function in lean subjects after adjustment - assuming no changes in other independent variables 1 s.d. increase in DHEA-S was associated with 13%-s.d. decrease in creatinine clearance (P = 0.004). Testosterone decreased across tertiles of creatinine clearance only in the crude analysis of nonlean (BMI greater than median) subjects (P < 0.001). The adjusted regression analysis that assumed no changes in other independent variables showed that 1 s.d. increase in total testosterone was associated with 11%-s.d. decrease in creatinine clearance of nonlean men (P = 0.006). Factor analysis confirmed an inverse association of renal function with both sex steroids and a different pattern of their loadings on glomerular filtration-related factors in lean (DHEA-S) and nonlean (testosterone) subjects. Conclusions: Our data may suggest that androgens are inversely associated with estimated renal function in apparently healthy men without history of cardiovascular disease. © 2009 American Journal of Hypertension, Ltd.
- Description: C1
- Kremer, Peter, Bell, Andrew, Sanigorski, Andrea, Swinburn, Boyd
- Authors: Kremer, Peter , Bell, Andrew , Sanigorski, Andrea , Swinburn, Boyd
- Date: 2006
- Type: Text , Journal article
- Relation: International Journal of Obesity Vol. 30, no. 4 (2006), p. 603-605
- Full Text: false
- Reviewed:
- Description: 2003002882
- Sanigorski, Andrea, Bell, Colin, Kremer, Peter, Swinburn, Boyd
- Authors: Sanigorski, Andrea , Bell, Colin , Kremer, Peter , Swinburn, Boyd
- Date: 2007
- Type: Text , Journal article
- Relation: International Journal of Obesity Vol. 31, no. (May 2007), p. S38-S38
- Full Text: false
- Reviewed:
- Description: C1
Small molecules, big effects: The role of microRNAs in regulation of cardiomyocyte death
- Skommer, Joanna, Rana, Indrajeetsinh, Marques, Francine, Zhu, Wenliang, Du, Zhimin, Charchar, Fadi
- Authors: Skommer, Joanna , Rana, Indrajeetsinh , Marques, Francine , Zhu, Wenliang , Du, Zhimin , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: Cell Death and Disease Vol. 5, no. 7 (2014), p. e1325
- Full Text:
- Reviewed:
- Description: MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranscriptional regulation of gene expression, and exerting regulatory roles in plethora of biological processes. In recent years, miRNAs have received increased attention for their crucial role in health and disease, including in cardiovascular disease. This review summarizes the role of miRNAs in regulation of cardiac cell death/cell survival pathways, including apoptosis, autophagy and necrosis. It is envisaged that these miRNAs may explain the mechanisms behind the pathogenesis of many cardiac diseases, and, most importantly, may provide new avenues for therapeutic intervention that will limit cardiomyocyte cell death before it irreversibly affects cardiac function. Through an indepth literature analysis coupled with integrative bioinformatics (pathway and synergy analysis), we dissect here the landscape of complex relationships between the apoptosis-regulating miRNAs in the context of cardiomyocyte cell death (including regulation of autophagy-apoptosis cross talk), and examine the gaps in our current understanding that will guide future investigations.
- Description: C1
- Authors: Skommer, Joanna , Rana, Indrajeetsinh , Marques, Francine , Zhu, Wenliang , Du, Zhimin , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: Cell Death and Disease Vol. 5, no. 7 (2014), p. e1325
- Full Text:
- Reviewed:
- Description: MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranscriptional regulation of gene expression, and exerting regulatory roles in plethora of biological processes. In recent years, miRNAs have received increased attention for their crucial role in health and disease, including in cardiovascular disease. This review summarizes the role of miRNAs in regulation of cardiac cell death/cell survival pathways, including apoptosis, autophagy and necrosis. It is envisaged that these miRNAs may explain the mechanisms behind the pathogenesis of many cardiac diseases, and, most importantly, may provide new avenues for therapeutic intervention that will limit cardiomyocyte cell death before it irreversibly affects cardiac function. Through an indepth literature analysis coupled with integrative bioinformatics (pathway and synergy analysis), we dissect here the landscape of complex relationships between the apoptosis-regulating miRNAs in the context of cardiomyocyte cell death (including regulation of autophagy-apoptosis cross talk), and examine the gaps in our current understanding that will guide future investigations.
- Description: C1
- Ohno, Sayaka, Hasegawa, Shoto, Liu, Huihua, Ishihara, Kazuhiko, Yusa, Shin-ichi
- Authors: Ohno, Sayaka , Hasegawa, Shoto , Liu, Huihua , Ishihara, Kazuhiko , Yusa, Shin-ichi
- Date: 2015
- Type: Text , Journal article
- Relation: Polymer Journal Vol. 47, no. 1 (2015), p. 71-76
- Full Text: false
- Reviewed:
- Description: Poly(2-(methacryloyloxy)ethyl phosphorylcholine)-block-poly(cholesteryl 6-methacryloyloxyhexanoate) (PMPC 82 -b-PChM n) copolymers with different PChM block lengths were prepared via reversible addition-fragmentation chain transfer controlled/living radical polymerization using a PMPC-based macro-chain transfer agent. The subscript number and n (=3 and 6) refer to the degree of polymerization of the PMPC and PChM blocks, respectively. PMPC 82 -b-PChM n cannot dissolve in water directly due to the strong hydrophobic nature of the PChM block. To prepare the aqueous solution, the diblock copolymer was dissolved in an organic solvent and then dialyzed against pure water. These diblock copolymers formed spherical and rod-like micelles in water, depending on the composition of cholesteryl (Chol) group in the polymer. The prepared aggregates were characterized using static light scattering, dynamic light scattering, transmission electron microscopy and fluorescence probe techniques. The characterization results suggest that the morphology of the polymer aggregates can be controlled from spherical to rod-like micelles by increasing the number of Chol groups in the polymer.
- Liddicoat, Douglas, Kyparissoudis, Konstantinos, Berzins, Stuart, Cole, Timothy, Godfrey, Dale
- Authors: Liddicoat, Douglas , Kyparissoudis, Konstantinos , Berzins, Stuart , Cole, Timothy , Godfrey, Dale
- Date: 2014
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 92, no. 10 (2014), p. 825-836
- Full Text: false
- Reviewed:
- Description: Glucocorticoids (GCs) are powerful inhibitors of inflammation and immunity. Although glucocorticoid-induced cell death (GICD) is an important part of GCs actions, the cell types and molecular mechanisms involved are not well understood. Untranslated exon 1A3 of the human glucocorticoid receptor (GR) gene is a major determinant of GICD in GICD-sensitive human cancer cell lines, operating to dynamically upregulate GR levels in response to GCs. We measured the GICD sensitivity of freshly isolated peripheral blood mononuclear cells and thymocytes to dexamethasone in vitro, relating this to GR exon 1A3 expression. A clear GICD sensitivity hierarchy was detected: B cells>thymocytes/natural killer (NK) cells>peripheral T cells. Within thymocyte populations, GICD sensitivity decreased with maturation. Interestingly, NK cell subsets were differentially sensitive to GICD, with CD16 + CD56 int (cytotoxic) NK cells being highly resistant to GICD, whereas CD16-CD56 hi (cytokine producing) NK cells were highly sensitive (similar to B cells). B-cell GICD was rescued by co-culture with interleukin-4. Strikingly, although no significant increases in GR protein were observed during 48 h of culture of GICD-sensitive and-resistant cells alike, GR 1A3 expression was increased over pre-culture levels in a manner directly proportional to the GICD sensitivity of each cell type. Accordingly, this is the first evidence that the GR exon 1A3 promoter is differentially regulated during thymic development and maturation of human T cells. Furthermore, human peripheral blood B cells are exquisitely GICD-sensitive in vitro, giving new insight into how GCs may downregulate immunity. Collectively, these data show that GR 1A3 expression is tied with GICD sensitivity in human lymphocytes, underscoring the potential for GR 1A3 expression to be used as a biomarker for sensitivity to GICD. © 2014 Australasian Society for Immunology Inc.
An investigation of the effects of stage of ensilage on Nassella neesiana seeds, for reducing seed viability and injury to livestock
- Weller, Sandra, Florentine, Singarayer, Sillitoe, Jim, Grech, Charles, McLaren, David
- Authors: Weller, Sandra , Florentine, Singarayer , Sillitoe, Jim , Grech, Charles , McLaren, David
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-7
- Full Text:
- Reviewed:
- Description: The noxious weed Nassella neesiana is established on a wide range of productive land throughout southeastern Australia. N. neesiana seeds, when mature, are sharp, causing injury to livestock, thus posing a problem in fodder bales. To reduce infestations of agricultural weeds in situ, production of silage from weed-infested pastures is practised as part of integrated weed management (IWM). However, there is little data to demonstrate whether this process is useful to reduce infestations or the harmful properties of N. neesiana. Therefore, the minimum duration of ensilage required to reduce the viability of N. neesiana seeds was investigated, both with and without addition of ensilage inoculants in this process. Also, the decreasing propensity of the seeds to injure livestock, after various times and conditions of ensilage, was assessed. Ensilage inoculant reduced seed germination probability to zero after 35 days. When no inoculant was added, zero viability was achieved after 42 days. A qualitative assessment of the hardness of ensilaged seeds found seed husks were softer (and therefore safer) after 42 days, whether inoculant was used or not. Therefore, we suggest that both the viability of N. neesiana seeds and hardness of seed casings are significantly reduced after 42 days, thereby reducing the risks of seed dispersal and injury to livestock.
- Authors: Weller, Sandra , Florentine, Singarayer , Sillitoe, Jim , Grech, Charles , McLaren, David
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-7
- Full Text:
- Reviewed:
- Description: The noxious weed Nassella neesiana is established on a wide range of productive land throughout southeastern Australia. N. neesiana seeds, when mature, are sharp, causing injury to livestock, thus posing a problem in fodder bales. To reduce infestations of agricultural weeds in situ, production of silage from weed-infested pastures is practised as part of integrated weed management (IWM). However, there is little data to demonstrate whether this process is useful to reduce infestations or the harmful properties of N. neesiana. Therefore, the minimum duration of ensilage required to reduce the viability of N. neesiana seeds was investigated, both with and without addition of ensilage inoculants in this process. Also, the decreasing propensity of the seeds to injure livestock, after various times and conditions of ensilage, was assessed. Ensilage inoculant reduced seed germination probability to zero after 35 days. When no inoculant was added, zero viability was achieved after 42 days. A qualitative assessment of the hardness of ensilaged seeds found seed husks were softer (and therefore safer) after 42 days, whether inoculant was used or not. Therefore, we suggest that both the viability of N. neesiana seeds and hardness of seed casings are significantly reduced after 42 days, thereby reducing the risks of seed dispersal and injury to livestock.
Specific humoral response of hosts with variable schistosomiasis susceptibility
- Driguez, Patrick, McWilliam, Hamish, Gaze, Soraya, Piedrafita, David, Pearson, Mark, Nakajima, Rie, Duke, Mary, Trieu, Angela, Doolan, Denise, Cardoso, Fernanda, Jasinskas, Algis, Gobert, Geoffrey, Felgner, Philip, Loukas, Alex, Meeusen, Els, McManus, Donald
- Authors: Driguez, Patrick , McWilliam, Hamish , Gaze, Soraya , Piedrafita, David , Pearson, Mark , Nakajima, Rie , Duke, Mary , Trieu, Angela , Doolan, Denise , Cardoso, Fernanda , Jasinskas, Algis , Gobert, Geoffrey , Felgner, Philip , Loukas, Alex , Meeusen, Els , McManus, Donald
- Date: 2016
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 94, no. 1 (2016), p. 52-65
- Full Text:
- Reviewed:
- Description: The schistosome blood flukes are some of the largest global causes of parasitic morbidity. Further study of the specific antibody response during schistosomiasis may yield the vaccines and diagnostics needed to combat this disease. Therefore, for the purposes of antigen discovery, sera and antibody-secreting cell (ASC) probes from semi-permissive rats and sera from susceptible mice were used to screen a schistosome protein microarray. Following Schistosoma japonicum infection, rats had reduced pathology, increased antibody responses and broader antigen recognition profiles compared with mice. With successive infections, rat global serological reactivity and the number of recognized antigens increased. The local antibody response in rat skin and lung, measured with ASC probes, increased after parasite migration and contributed antigen-specific antibodies to the multivalent serological response. In addition, the temporal variation of anti-parasite serum antibodies after infection and reinfection followed patterns that appear related to the antigen driving the response. Among the 29 antigens differentially recognized by the infected hosts were numerous known vaccine candidates, drug targets and several S. japonicum homologs of human schistosomiasis resistance markers - the tegument allergen-like proteins. From this set, we prioritized eight proteins that may prove to be novel schistosome vaccine and diagnostic antigens. © 2016 Australasian Society for Immunology Inc. All rights reserved.
- Authors: Driguez, Patrick , McWilliam, Hamish , Gaze, Soraya , Piedrafita, David , Pearson, Mark , Nakajima, Rie , Duke, Mary , Trieu, Angela , Doolan, Denise , Cardoso, Fernanda , Jasinskas, Algis , Gobert, Geoffrey , Felgner, Philip , Loukas, Alex , Meeusen, Els , McManus, Donald
- Date: 2016
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 94, no. 1 (2016), p. 52-65
- Full Text:
- Reviewed:
- Description: The schistosome blood flukes are some of the largest global causes of parasitic morbidity. Further study of the specific antibody response during schistosomiasis may yield the vaccines and diagnostics needed to combat this disease. Therefore, for the purposes of antigen discovery, sera and antibody-secreting cell (ASC) probes from semi-permissive rats and sera from susceptible mice were used to screen a schistosome protein microarray. Following Schistosoma japonicum infection, rats had reduced pathology, increased antibody responses and broader antigen recognition profiles compared with mice. With successive infections, rat global serological reactivity and the number of recognized antigens increased. The local antibody response in rat skin and lung, measured with ASC probes, increased after parasite migration and contributed antigen-specific antibodies to the multivalent serological response. In addition, the temporal variation of anti-parasite serum antibodies after infection and reinfection followed patterns that appear related to the antigen driving the response. Among the 29 antigens differentially recognized by the infected hosts were numerous known vaccine candidates, drug targets and several S. japonicum homologs of human schistosomiasis resistance markers - the tegument allergen-like proteins. From this set, we prioritized eight proteins that may prove to be novel schistosome vaccine and diagnostic antigens. © 2016 Australasian Society for Immunology Inc. All rights reserved.
Response of Chloris truncata to moisture stress, elevated carbon dioxide and herbicide application
- Weller, Sandra, Florentine, Singarayer, Mutti, Navneet, Jha, Prashant, Chauhan, Bhagirath
- Authors: Weller, Sandra , Florentine, Singarayer , Mutti, Navneet , Jha, Prashant , Chauhan, Bhagirath
- Date: 2019
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 9, no. 1 (2019), p. 1-10
- Full Text:
- Reviewed:
- Description: Herbicide resistance has been observed in Chloris truncata, an Australian native C4 grass and a summer-fallow weed, which is common in no-till agriculture situations where herbicides are involved in crop management. To investigate the role of drought and increased atmospheric carbon dioxide (CO2) in determining weed growth, three trials were conducted using a ‘glyphosate-resistant’ and a ‘glyphosate-susceptible’ biotype. The first two trials tested the effect of herbicide (glyphosate) application on plant survival and growth under moisture stress and elevated CO2 respectively. A third trial investigated the effect on plant growth and reproduction under conditions of moisture stress and elevated CO2 in the absence of herbicide. In the first trial, water was withheld from half of the plants prior to application of glyphosate to all plants, and in the second trial plants were grown in either ambient (450 ppm) or elevated CO2 levels (750 ppm) prior to, and following, herbicide application. In both biotypes, herbicide effectiveness was reduced when plants were subjected to moisture stress or if grown in elevated CO2. Plant productivity, as measured by dry biomass per plant, was reduced with moisture stress, but increased with elevated CO2. In the third trial, growth rate, biomass and seed production were higher in the susceptible biotype compared to the resistant biotype. This suggests that a superior ability to resist herbicides may come at a cost to overall plant fitness. The results indicate that control of this weed may become difficult in the future as climatic conditions change. Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-47237-x.
- Authors: Weller, Sandra , Florentine, Singarayer , Mutti, Navneet , Jha, Prashant , Chauhan, Bhagirath
- Date: 2019
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 9, no. 1 (2019), p. 1-10
- Full Text:
- Reviewed:
- Description: Herbicide resistance has been observed in Chloris truncata, an Australian native C4 grass and a summer-fallow weed, which is common in no-till agriculture situations where herbicides are involved in crop management. To investigate the role of drought and increased atmospheric carbon dioxide (CO2) in determining weed growth, three trials were conducted using a ‘glyphosate-resistant’ and a ‘glyphosate-susceptible’ biotype. The first two trials tested the effect of herbicide (glyphosate) application on plant survival and growth under moisture stress and elevated CO2 respectively. A third trial investigated the effect on plant growth and reproduction under conditions of moisture stress and elevated CO2 in the absence of herbicide. In the first trial, water was withheld from half of the plants prior to application of glyphosate to all plants, and in the second trial plants were grown in either ambient (450 ppm) or elevated CO2 levels (750 ppm) prior to, and following, herbicide application. In both biotypes, herbicide effectiveness was reduced when plants were subjected to moisture stress or if grown in elevated CO2. Plant productivity, as measured by dry biomass per plant, was reduced with moisture stress, but increased with elevated CO2. In the third trial, growth rate, biomass and seed production were higher in the susceptible biotype compared to the resistant biotype. This suggests that a superior ability to resist herbicides may come at a cost to overall plant fitness. The results indicate that control of this weed may become difficult in the future as climatic conditions change. Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-47237-x.
Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
- Stanley, Christopher, Maghzal, Ghassan, Ayer, Anita, Talib, Jihan, Giltrap, Andrew, Shengule, Sudhir, Wolhuter, Kathryn, Wang, Yutang, Chadha, Preet, Suarna, Cacang, Prysyazhna, Oleksandra, Scotcher, Jenna, Dunn, Louise, Prado, Fernanda, Nguyen, Nghi, Odiba, Jephthah, Baell, Johathan, Stasch, Johannes-Peter, Yamamoto, Yorihiro, Di Mascio, Paolo, Eaton, Philip, Payne, Richard, Stocker, Roland
- Authors: Stanley, Christopher , Maghzal, Ghassan , Ayer, Anita , Talib, Jihan , Giltrap, Andrew , Shengule, Sudhir , Wolhuter, Kathryn , Wang, Yutang , Chadha, Preet , Suarna, Cacang , Prysyazhna, Oleksandra , Scotcher, Jenna , Dunn, Louise , Prado, Fernanda , Nguyen, Nghi , Odiba, Jephthah , Baell, Johathan , Stasch, Johannes-Peter , Yamamoto, Yorihiro , Di Mascio, Paolo , Eaton, Philip , Payne, Richard , Stocker, Roland
- Date: 2019
- Type: Text , Journal article , Letter
- Relation: Nature Vol. 566, no. 7745 (2019), p. 548-552
- Full Text:
- Reviewed:
- Description: Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
- Authors: Stanley, Christopher , Maghzal, Ghassan , Ayer, Anita , Talib, Jihan , Giltrap, Andrew , Shengule, Sudhir , Wolhuter, Kathryn , Wang, Yutang , Chadha, Preet , Suarna, Cacang , Prysyazhna, Oleksandra , Scotcher, Jenna , Dunn, Louise , Prado, Fernanda , Nguyen, Nghi , Odiba, Jephthah , Baell, Johathan , Stasch, Johannes-Peter , Yamamoto, Yorihiro , Di Mascio, Paolo , Eaton, Philip , Payne, Richard , Stocker, Roland
- Date: 2019
- Type: Text , Journal article , Letter
- Relation: Nature Vol. 566, no. 7745 (2019), p. 548-552
- Full Text:
- Reviewed:
- Description: Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
Knockdown of stem cell regulator Oct4A in ovarian cancer reveals cellular reprogramming associated with key regulators of cytoskeleton-extracellular matrix remodelling
- Samardzija, Chantel, Greening, David, Escalona, Ruth, Chen, Maoshan, Bilandzic, Maree, Luwor, Rodney, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Samardzija, Chantel , Greening, David , Escalona, Ruth , Chen, Maoshan , Bilandzic, Maree , Luwor, Rodney , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. (2017), p. 1-18
- Full Text:
- Reviewed:
- Description: Oct4A is a master regulator of self-renewal and pluripotency in embryonic stem cells. It is a well-established marker for cancer stem cell (CSC) in malignancies. Recently, using a loss of function studies, we have demonstrated key roles for Oct4A in tumor cell survival, metastasis and chemoresistance in in vitro and in vivo models of ovarian cancer. In an effort to understand the regulatory role of Oct4A in tumor biology, we employed the use of an ovarian cancer shRNA Oct4A knockdown cell line (HEY Oct4A KD) and a global mass spectrometry (MS)-based proteomic analysis to investigate novel biological targets of Oct4A in HEY samples (cell lysates, secretomes and mouse tumor xenografts). Based on significant differential expression, pathway and protein network analyses, and comprehensive literature search we identified key proteins involved with biologically relevant functions of Oct4A in tumor biology. Across all preparations of HEY Oct4A KD samples significant alterations in protein networks associated with cytoskeleton, extracellular matrix (ECM), proliferation, adhesion, metabolism, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and drug resistance was observed. This comprehensive proteomics study for the first time presents the Oct4A associated proteome and expands our understanding on the biological role of this stem cell regulator in carcinomas. © 2017 The Author(s).
- Authors: Samardzija, Chantel , Greening, David , Escalona, Ruth , Chen, Maoshan , Bilandzic, Maree , Luwor, Rodney , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. (2017), p. 1-18
- Full Text:
- Reviewed:
- Description: Oct4A is a master regulator of self-renewal and pluripotency in embryonic stem cells. It is a well-established marker for cancer stem cell (CSC) in malignancies. Recently, using a loss of function studies, we have demonstrated key roles for Oct4A in tumor cell survival, metastasis and chemoresistance in in vitro and in vivo models of ovarian cancer. In an effort to understand the regulatory role of Oct4A in tumor biology, we employed the use of an ovarian cancer shRNA Oct4A knockdown cell line (HEY Oct4A KD) and a global mass spectrometry (MS)-based proteomic analysis to investigate novel biological targets of Oct4A in HEY samples (cell lysates, secretomes and mouse tumor xenografts). Based on significant differential expression, pathway and protein network analyses, and comprehensive literature search we identified key proteins involved with biologically relevant functions of Oct4A in tumor biology. Across all preparations of HEY Oct4A KD samples significant alterations in protein networks associated with cytoskeleton, extracellular matrix (ECM), proliferation, adhesion, metabolism, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and drug resistance was observed. This comprehensive proteomics study for the first time presents the Oct4A associated proteome and expands our understanding on the biological role of this stem cell regulator in carcinomas. © 2017 The Author(s).
National income inequality predicts cultural variation in mouth to mouth kissing
- Watkins, Christopher, Leongómez, Juan, Bovet, Jeanne, Żelaźniewicz, Agnieszka, Korbmacher, Max, Varella, Marco, Fernandez, Ana, Wagstaff, Danielle, Bolgan, Samuela
- Authors: Watkins, Christopher , Leongómez, Juan , Bovet, Jeanne , Żelaźniewicz, Agnieszka , Korbmacher, Max , Varella, Marco , Fernandez, Ana , Wagstaff, Danielle , Bolgan, Samuela
- Date: 2019
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 9, no. 1 (2019), p. 1-9
- Full Text:
- Reviewed:
- Description: Romantic mouth-to-mouth kissing is culturally widespread, although not a human universal, and may play a functional role in assessing partner health and maintaining long-term pair bonds. Use and appreciation of kissing may therefore vary according to whether the environment places a premium on good health and partner investment. Here, we test for cultural variation (13 countries from six continents) in these behaviours/attitudes according to national health (historical pathogen prevalence) and both absolute (GDP) and relative wealth (GINI). Our data reveal that kissing is valued more in established relationships than it is valued during courtship. Also, consistent with the pair bonding hypothesis of the function of romantic kissing, relative poverty (income inequality) predicts frequency of kissing across romantic relationships. When aggregated, the predicted relationship between income inequality and kissing frequency (r = 0.67, BCa 95% CI[0.32,0.89]) was over five times the size of the null correlations between income inequality and frequency of hugging/cuddling and sex. As social complexity requires monitoring resource competition among large groups and predicts kissing prevalence in remote societies, this gesture may be important in the maintenance of long-term pair bonds in specific environments.
- Authors: Watkins, Christopher , Leongómez, Juan , Bovet, Jeanne , Żelaźniewicz, Agnieszka , Korbmacher, Max , Varella, Marco , Fernandez, Ana , Wagstaff, Danielle , Bolgan, Samuela
- Date: 2019
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 9, no. 1 (2019), p. 1-9
- Full Text:
- Reviewed:
- Description: Romantic mouth-to-mouth kissing is culturally widespread, although not a human universal, and may play a functional role in assessing partner health and maintaining long-term pair bonds. Use and appreciation of kissing may therefore vary according to whether the environment places a premium on good health and partner investment. Here, we test for cultural variation (13 countries from six continents) in these behaviours/attitudes according to national health (historical pathogen prevalence) and both absolute (GDP) and relative wealth (GINI). Our data reveal that kissing is valued more in established relationships than it is valued during courtship. Also, consistent with the pair bonding hypothesis of the function of romantic kissing, relative poverty (income inequality) predicts frequency of kissing across romantic relationships. When aggregated, the predicted relationship between income inequality and kissing frequency (r = 0.67, BCa 95% CI[0.32,0.89]) was over five times the size of the null correlations between income inequality and frequency of hugging/cuddling and sex. As social complexity requires monitoring resource competition among large groups and predicts kissing prevalence in remote societies, this gesture may be important in the maintenance of long-term pair bonds in specific environments.
A novel Y-specific long non-coding RNA associated with cellular lipid accumulation in HepG2 cells and Atherosclerosis-related genes
- Molina, Elsa, Chew, Guat, Myers, Stephen, Clarence, Elyse, Eales, James, Tomaszewski, Maciej, Charchar, Fadi
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
- Koay, Hui-Fern, Gherardin, Nicholas, Enders, Anselm, Loh, Liyen, Mackay, Laura, Almeida, Catarina, Russ, Brendan, Nold-Petry, Claudia, Nold, Marcel, Bedoui, Sammy, Chen, Zhenjun, Corbett, Alexandra, Eckle, Sidonia, Meehan, Bronwyn, d'Udekem, Yves, Konstantinov, Igor, Lappas, Martha, Liu, Ligong, Goodnow, Chris, Fairlie, David, Rossjohn, Jamie, Chong, Mark, Kedzierska, Katherine, Berzins, Stuart, Belz, Gabrielle, McCluskey, James, Uldrich, Adam, Godfrey, Dale, Pellicci, Daniel
- Authors: Koay, Hui-Fern , Gherardin, Nicholas , Enders, Anselm , Loh, Liyen , Mackay, Laura , Almeida, Catarina , Russ, Brendan , Nold-Petry, Claudia , Nold, Marcel , Bedoui, Sammy , Chen, Zhenjun , Corbett, Alexandra , Eckle, Sidonia , Meehan, Bronwyn , d'Udekem, Yves , Konstantinov, Igor , Lappas, Martha , Liu, Ligong , Goodnow, Chris , Fairlie, David , Rossjohn, Jamie , Chong, Mark , Kedzierska, Katherine , Berzins, Stuart , Belz, Gabrielle , McCluskey, James , Uldrich, Adam , Godfrey, Dale , Pellicci, Daniel
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Immunology Vol. 17, no. 11 (2016), p. 1300-1311
- Full Text:
- Reviewed:
- Description: Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.
- Authors: Koay, Hui-Fern , Gherardin, Nicholas , Enders, Anselm , Loh, Liyen , Mackay, Laura , Almeida, Catarina , Russ, Brendan , Nold-Petry, Claudia , Nold, Marcel , Bedoui, Sammy , Chen, Zhenjun , Corbett, Alexandra , Eckle, Sidonia , Meehan, Bronwyn , d'Udekem, Yves , Konstantinov, Igor , Lappas, Martha , Liu, Ligong , Goodnow, Chris , Fairlie, David , Rossjohn, Jamie , Chong, Mark , Kedzierska, Katherine , Berzins, Stuart , Belz, Gabrielle , McCluskey, James , Uldrich, Adam , Godfrey, Dale , Pellicci, Daniel
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Immunology Vol. 17, no. 11 (2016), p. 1300-1311
- Full Text:
- Reviewed:
- Description: Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.
Projected increase in El Niño-driven tropical cyclone frequency in the Pacific
- Chand, Savin, Tory, Kevin, Ye, Hua, Walsh, Kevin
- Authors: Chand, Savin , Tory, Kevin , Ye, Hua , Walsh, Kevin
- Date: 2017
- Type: Text , Journal article
- Relation: Nature Climate Change Vol. 7, no. 2 (2017), p. 123-127
- Full Text: false
- Reviewed:
- Description: The El Niño/Southern Oscillation (ENSO) drives substantial variability in tropical cyclone (TC) activity around the world. However, it remains uncertain how the projected future changes in ENSO under greenhouse warming will affect TC activity, apart from an expectation that the overall frequency of TCs is likely to decrease for most ocean basins. Here we show robust changes in ENSO-driven variability in TC occurrence by the late twenty-first century. In particular, we show that TCs become more frequent (â 1/420-40%) during future-climate El Niño events compared with present-climate El Niño events - and less frequent during future-climate La Niña events - around a group of small island nations (for example, Fiji, Vanuatu, Marshall Islands and Hawaii) in the Pacific. We examine TCs across 20 models from the Coupled Model Intercomparison Project phase 5 database, forced under historical and greenhouse warming conditions. The 12 most realistic models identified show a strong consensus on El Niño-driven changes in future-climate large-scale environmental conditions that modulate development of TCs over the off-equatorial western Pacific and the central North Pacific regions. These results have important implications for climate change and adaptation pathways for the vulnerable Pacific island nations. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Monotreme glucagon-like peptide-1 in venom and gut : One gene - Two very different functions
- Tsend-Ayush, Enkhjargal, He, Chuan, Myers, Mark, Andrikopoulos, Sof, Wong, Nicole, Sexton, Patrick, Wootten, Denise, Forbes, Briony, Grutzner, Frank
- Authors: Tsend-Ayush, Enkhjargal , He, Chuan , Myers, Mark , Andrikopoulos, Sof , Wong, Nicole , Sexton, Patrick , Wootten, Denise , Forbes, Briony , Grutzner, Frank
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-12
- Full Text:
- Reviewed:
- Description: The importance of Glucagon like peptide 1 (GLP-1) for metabolic control and insulin release sparked the evolution of genes mimicking GLP-1 action in venomous species (e.g. Exendin-4 in Heloderma suspectum (gila monster)). We discovered that platypus and echidna express a single GLP-1 peptide in both intestine and venom. Specific changes in GLP-1 of monotreme mammals result in resistance to DPP-4 cleavage which is also observed in the GLP-1 like Exendin-4 expressed in Heloderma venom. Remarkably we discovered that monotremes evolved an alternative mechanism to degrade GLP-1. We also show that monotreme GLP-1 stimulates insulin release in cultured rodent islets, but surprisingly shows low receptor affinity and bias toward Erk signaling. We propose that these changes in monotreme GLP-1 are the result of conflicting function of this peptide in metabolic control and venom. This evolutionary path is fundamentally different from the generally accepted idea that conflicting functions in a single gene favour duplication and diversification, as is the case for Exendin-4 in gila monster. This provides novel insight into the remarkably different metabolic control mechanism and venom function in monotremes and an unique example of how different selective pressures act upon a single gene in the absence of gene duplication. © The Author(s) 2016.
- Authors: Tsend-Ayush, Enkhjargal , He, Chuan , Myers, Mark , Andrikopoulos, Sof , Wong, Nicole , Sexton, Patrick , Wootten, Denise , Forbes, Briony , Grutzner, Frank
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-12
- Full Text:
- Reviewed:
- Description: The importance of Glucagon like peptide 1 (GLP-1) for metabolic control and insulin release sparked the evolution of genes mimicking GLP-1 action in venomous species (e.g. Exendin-4 in Heloderma suspectum (gila monster)). We discovered that platypus and echidna express a single GLP-1 peptide in both intestine and venom. Specific changes in GLP-1 of monotreme mammals result in resistance to DPP-4 cleavage which is also observed in the GLP-1 like Exendin-4 expressed in Heloderma venom. Remarkably we discovered that monotremes evolved an alternative mechanism to degrade GLP-1. We also show that monotreme GLP-1 stimulates insulin release in cultured rodent islets, but surprisingly shows low receptor affinity and bias toward Erk signaling. We propose that these changes in monotreme GLP-1 are the result of conflicting function of this peptide in metabolic control and venom. This evolutionary path is fundamentally different from the generally accepted idea that conflicting functions in a single gene favour duplication and diversification, as is the case for Exendin-4 in gila monster. This provides novel insight into the remarkably different metabolic control mechanism and venom function in monotremes and an unique example of how different selective pressures act upon a single gene in the absence of gene duplication. © The Author(s) 2016.
Unique proteome signature of post-chemotherapy ovarian cancer ascites-derived tumor cells
- Ahmed, Nuzhat, Greening, David, Samardzija, Chantel, Escalona, Ruth, Chen, Maoshan, Findlay, Jock, Kannourakis, George
- Authors: Ahmed, Nuzhat , Greening, David , Samardzija, Chantel , Escalona, Ruth , Chen, Maoshan , Findlay, Jock , Kannourakis, George
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-13
- Full Text:
- Reviewed:
- Description: Eighty % of ovarian cancer patients diagnosed at an advanced-stage have complete remission after initial surgery and chemotherapy. However, most patients die within <5 years due to episodes of recurrences resulting from the growth of residual chemoresistant cells. In an effort to identify mechanisms associated with chemoresistance and recurrence, we compared the expression of proteins in ascites-derived tumor cells isolated from advanced-stage ovarian cancer patients obtained at diagnosis (chemonaive, CN) and after chemotherapy treatments (chemoresistant/at recurrence, CR) by using in-depth, high-resolution label-free quantitative proteomic profiling. A total of 2,999 proteins were identified. Using a stringent selection criterion to define only significantly differentially expressed proteins, we report identification of 353 proteins. There were significant differences in proteins encoding for immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of metabolic pathways, DNA repair mechanisms and energy metabolism pathways in CR tumor cells. In conclusion, this is the first proteomics study to comprehensively analyze ascites-derived tumor cells from CN and CR ovarian cancer patients.
- Authors: Ahmed, Nuzhat , Greening, David , Samardzija, Chantel , Escalona, Ruth , Chen, Maoshan , Findlay, Jock , Kannourakis, George
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-13
- Full Text:
- Reviewed:
- Description: Eighty % of ovarian cancer patients diagnosed at an advanced-stage have complete remission after initial surgery and chemotherapy. However, most patients die within <5 years due to episodes of recurrences resulting from the growth of residual chemoresistant cells. In an effort to identify mechanisms associated with chemoresistance and recurrence, we compared the expression of proteins in ascites-derived tumor cells isolated from advanced-stage ovarian cancer patients obtained at diagnosis (chemonaive, CN) and after chemotherapy treatments (chemoresistant/at recurrence, CR) by using in-depth, high-resolution label-free quantitative proteomic profiling. A total of 2,999 proteins were identified. Using a stringent selection criterion to define only significantly differentially expressed proteins, we report identification of 353 proteins. There were significant differences in proteins encoding for immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of metabolic pathways, DNA repair mechanisms and energy metabolism pathways in CR tumor cells. In conclusion, this is the first proteomics study to comprehensively analyze ascites-derived tumor cells from CN and CR ovarian cancer patients.
Renal nerves contribute to hypertension in Schlager BPH/2J mice
- Gueguen, Cindy, Jackson, Kristy, Marques, Francine, Eikelis, Nina, Phillips, Sarah, Stevenson, Emily, Charchar, Fadi, Lambert, Gavin, Davern, Pamela, Head, Geoffrey
- Authors: Gueguen, Cindy , Jackson, Kristy , Marques, Francine , Eikelis, Nina , Phillips, Sarah , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Davern, Pamela , Head, Geoffrey
- Date: 2019
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 42, no. 3 (2019), p. 306-318
- Full Text:
- Reviewed:
- Description: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was −10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and −2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8–10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (−12 vs −3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.
- Authors: Gueguen, Cindy , Jackson, Kristy , Marques, Francine , Eikelis, Nina , Phillips, Sarah , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Davern, Pamela , Head, Geoffrey
- Date: 2019
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 42, no. 3 (2019), p. 306-318
- Full Text:
- Reviewed:
- Description: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was −10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and −2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8–10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (−12 vs −3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.
Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- Pattaro, C, Teumer, A, Gorski, M, Chu, A.Y., Li, M, Mijatovic, V, Garnaas, M, Tin, A, Charchar, Fadi
- Authors: Pattaro, C , Teumer, A , Gorski, M , Chu, A.Y. , Li, M , Mijatovic, V , Garnaas, M , Tin, A , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Communications Vol. 7, no. (2016), p. 1-19
- Full Text:
- Reviewed:
- Description: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the Federation University Australia affiliate.
- Authors: Pattaro, C , Teumer, A , Gorski, M , Chu, A.Y. , Li, M , Mijatovic, V , Garnaas, M , Tin, A , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Communications Vol. 7, no. (2016), p. 1-19
- Full Text:
- Reviewed:
- Description: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the Federation University Australia affiliate.