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Article ; Online: Calcineurin regulates aldosterone production via dephosphorylation of NFATC4.

Berber, Mesut / Leng, Sining / Wengi, Agnieszka / Winter, Denise V / Odermatt, Alex / Beuschlein, Felix / Loffing, Johannes / Breault, David T / Penton, David

JCI insight

2023 Volume 8, Issue 14

Abstract: The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low ... ...

Abstract	The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K+-stimulated) expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.
MeSH term(s)	Animals ; Humans ; Mice ; Aldosterone/metabolism ; Calcineurin/metabolism ; Cytochrome P-450 CYP11B2/genetics ; Hyperkalemia ; NFATC Transcription Factors/genetics ; Tacrolimus/pharmacology
Chemical Substances	Aldosterone (4964P6T9RB) ; Calcineurin (EC 3.1.3.16) ; Cytochrome P-450 CYP11B2 (EC 1.14.15.4) ; NFATC Transcription Factors ; NFATC4 protein, human ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2023-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.157027
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Zona Glomerulosa-Derived Klotho Modulates Aldosterone Synthase Expression in Young Female Mice.

Daryadel, Arezoo / Tang, Cong / Xie, Ye / Peitzsch, Mirko / Fisi, Viktoria / Hantel, Constanze / Loffing-Cueni, Dominique / Breault, David T / Penton, David / Loffing, Johannes / Beuschlein, Felix

Endocrinology

2024 Volume 165, Issue 5

Abstract: Klotho plays a critical role in the regulation of ion and fluid homeostasis. A previous study reported that haplo-insufficiency of Klotho in mice results in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone, and high blood ... ...

Abstract	Klotho plays a critical role in the regulation of ion and fluid homeostasis. A previous study reported that haplo-insufficiency of Klotho in mice results in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone, and high blood pressure. This phenotype was presumed to be the result of diminished Klotho expression in zona glomerulosa (zG) cells of the adrenal cortex; however, systemic effects on adrenal aldosterone production could not be ruled out. To examine whether Klotho expressed in the zG is indeed a critical regulator of aldosterone synthesis, we generated a tamoxifen-inducible, zG-specific mouse model of Klotho deficiency by crossing Klotho-flox mice with Cyp11b2-CreERT mice (zG-Kl-KO). Tamoxifen-treated Cyp11b2-CreERT animals (zG-Cre) served as controls. Rosa26-mTmG reporter mice were used for Cre-dependent lineage-marking. Two weeks after tamoxifen induction, the specificity of the zG-Cre line was verified using immunofluorescence analysis to show that GFP expression was restricted to the zG. RNA in situ hybridization revealed a 65% downregulation of Klotho messenger RNA expression in the zG of zG-Kl-KO female mice at age 12 weeks compared to control mice. Despite this significant decrease, zG-Kl-KO mice exhibited no difference in plasma aldosterone levels. However, adrenal CYP11B2 expression and the CYP11B2 promotor regulatory transcription factors, NGFIB and Nurr1, were enhanced. Together with in vitro experiments, these results suggest that zG-derived Klotho modulates Cyp11b2 but does not evoke a systemic phenotype in young adult mice on a normal diet. Further studies are required to investigate the role of adrenal Klotho on aldosterone synthesis in aged animals.
MeSH term(s)	Female ; Mice ; Animals ; Zona Glomerulosa/metabolism ; Cytochrome P-450 CYP11B2/genetics ; Cytochrome P-450 CYP11B2/metabolism ; Aldosterone/metabolism ; Adrenal Cortex/metabolism ; Hyperaldosteronism/genetics ; Tamoxifen/pharmacology
Chemical Substances	Cytochrome P-450 CYP11B2 (EC 1.14.15.4) ; Aldosterone (4964P6T9RB) ; Tamoxifen (094ZI81Y45)
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqae040
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Article ; Online: Characterisation of meteorological drought at sub-catchment scale in Afghanistan using station-observed climate data.

Chen, Yun / Penton, David / Karim, Fazlul / Aryal, Santosh / Wahid, Shahriar / Taylor, Peter / Cuddy, Susan M

PloS one

2023 Volume 18, Issue 2, Page(s) e0280522

Abstract: Droughts have severely affected Afghanistan over the last four decades, leading to critical food shortages where two-thirds of the country's population are in a food crisis. Long years of conflict have lowered the country's ability to deal with hazards ... ...

Abstract	Droughts have severely affected Afghanistan over the last four decades, leading to critical food shortages where two-thirds of the country's population are in a food crisis. Long years of conflict have lowered the country's ability to deal with hazards such as drought which can rapidly escalate into disasters. Understanding the spatial and temporal distribution of droughts is needed to be able to respond effectively to disasters and plan for future occurrences. This study used Standardized Precipitation Evapotranspiration Index (SPEI) at monthly, seasonal and annual temporal scales to map the spatiotemporal change dynamics of drought characteristics (distribution, frequency, duration and severity) in Afghanistan. SPEI indices were mapped for river basins, disaggregated into 189 sub-catchments, using monthly precipitation and potential evapotranspiration derived from temperature station observations from 1980 to 2017. The results show these multi-dimensional drought characteristics vary along different years, change among sub-catchments, and differ across temporal scales. During the 38 years, the driest decade and period are 2000s and 1999-2022, respectively. The 2000-01 water year is the driest with the whole country experiencing 'severe' to 'extreme' drought, more than 53% (87 sub-catchments) suffering the worst drought in history, and about 58% (94 sub-catchments) having 'very frequent' drought (7 to 8 months) or 'extremely frequent' drought (9 to 10 months). The estimated seasonal duration and severity present significant variations across the study area and among the study period. The nation also suffers from recurring droughts with varying length and intensity in 2004, 2006, 2008 and most recently 2011. There is a trend towards increasing drought with longer duration and higher severity extending all over sub-catchments from southeast to north and central regions. These datasets and maps help to fill the knowledge gap on detailed sub-catchment scale meteorological drought characteristics in Afghanistan. The study findings improve our understanding of the influences of climate change on the drought dynamics and can guide catchment planning for reliable adaptation to and mitigation against future droughts.
MeSH term(s)	Droughts ; Afghanistan ; Meteorology ; Climate Change ; Adaptation, Physiological
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0280522
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Water access and household economic insecurity: conceptual framework and econometric analysis applied to rural Nepal

Fleming, David A. / Foran, Tira / Neupane, Nilhari / Rasul, Golam / Wahid, Shahriar M. / Penton, David J.

International Journal of Water Resources Development. 2023 Mar. 04, v. 39, no. 2 p.236-254

2023

Abstract: We develop a conceptual framework to understand linkages between water access and livelihood outcomes. We apply the framework to assess factors altering the likelihood of household indebtedness in rural Nepal, using survey data and probit statistical ... ...

Abstract	We develop a conceptual framework to understand linkages between water access and livelihood outcomes. We apply the framework to assess factors altering the likelihood of household indebtedness in rural Nepal, using survey data and probit statistical models. Controlling for different household characteristics, results show that in Nepal’s Kamala basin, an additional month of water adequate to sustain crops decreases by 5% the likelihood that an average household in our sample reports high indebtedness. We complement our findings by discussing interacting drivers of agricultural livelihood outcomes; options to improve water availability and access; and geographical targeting of investment in water access.
Keywords	basins ; econometrics ; livelihood ; surveys ; water ; Nepal ; Cross-sectional household data ; livelihoods ; regional analysis ; household indebtedness
Language	English
Dates of publication	2023-0304
Size	p. 236-254.
Publishing place	Routledge
Document type	Article ; Online
ZDB-ID	2016525-0
ISSN	1360-0648 ; 0790-0627
ISSN (online)	1360-0648
ISSN	0790-0627
DOI	10.1080/07900627.2021.1999217
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Calcineurin regulates aldosterone production via dephosphorylation of NFATC4

Mesut Berber / Sining Leng / Agnieszka Wengi / Denise V. Winter / Alex Odermatt / Felix Beuschlein / Johannes Loffing / David T. Breault / David Penton

JCI Insight, Vol 8, Iss

2023 Volume 14

Abstract	The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K+-stimulated) expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.
Keywords	Endocrinology ; Metabolism ; Medicine ; R
Subject code	570
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction: Sigala et al. A Comprehensive Investigation of Steroidogenic Signaling in Classical and New Experimental Cell Models of Adrenocortical Carcinoma.

Sigala, Sandra / Bothou, Christina / Penton, David / Abate, Andrea / Peitzsch, Mirko / Cosentini, Deborah / Tiberio, Guido A M / Bornstein, Stefan R / Berruti, Alfredo / Hantel, Constanze

Cells

2023 Volume 12, Issue 18

Abstract: The authors made the following changes to their paper [ ... ]. ...

Abstract	The authors made the following changes to their paper [...].
Language	English
Publishing date	2023-09-14
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12182274
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Article ; Online: Spatial proteomics finds CD155 and Endophilin-A1 as mediators of growth and invasion in medulloblastoma.

Capdeville, Charles / Russo, Linda / Penton, David / Migliavacca, Jessica / Zecevic, Milica / Gries, Alexandre / Neuhauss, Stephan Cf / Grotzer, Michael A / Baumgartner, Martin

Life science alliance

2022 Volume 5, Issue 6

Abstract: The composition of the plasma membrane (PM)-associated proteome of tumor cells determines cell-cell and cell-matrix interactions and the response to environmental cues. Whether the PM-associated proteome impacts the phenotype of Medulloblastoma (MB) ... ...

Abstract	The composition of the plasma membrane (PM)-associated proteome of tumor cells determines cell-cell and cell-matrix interactions and the response to environmental cues. Whether the PM-associated proteome impacts the phenotype of Medulloblastoma (MB) tumor cells and how it adapts in response to growth factor cues is poorly understood. Using a spatial proteomics approach, we observed that hepatocyte growth factor (HGF)-induced activation of the receptor tyrosine kinase c-MET in MB cells changes the abundance of transmembrane and membrane-associated proteins. The depletion of MAP4K4, a pro-migratory effector kinase downstream of c-MET, leads to a specific decrease of the adhesion and immunomodulatory receptor CD155 and of components of the fast-endophilin-mediated endocytosis (FEME) machinery in the PM-associated proteome of HGF-activated MB cells. The decreased surface expression of CD155 or of the fast-endophilin-mediated endocytosis effector endophilin-A1 reduces growth and invasiveness of MB tumor cells in the tissue context. These data thus describe a novel function of MAP4K4 in the control of the PM-associated proteome of tumor cells and identified two downstream effector mechanisms controlling proliferation and invasiveness of MB cells.
MeSH term(s)	Cerebellar Neoplasms ; Endocytosis ; Humans ; Intracellular Signaling Peptides and Proteins ; Medulloblastoma/metabolism ; Medulloblastoma/pathology ; Protein Serine-Threonine Kinases ; Proteome ; Proteomics
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Proteome ; MAP4K4 protein, human (EC 2.7.1.11) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202201380
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The floodplain inundation history of the Murray-Darling Basin through two-monthly maximum water depth maps.

Penton, David J / Teng, Jin / Ticehurst, Catherine / Marvanek, Steve / Freebairn, Andrew / Mateo, Cherry / Vaze, Jai / Yang, Ang / Khanam, Fathaha / Sengupta, Ashmita / Pollino, Carmel

Scientific data

2023 Volume 10, Issue 1, Page(s) 652

Abstract: With growing concerns over water management in rivers worldwide, researchers are seeking innovative solutions to monitor and understand changing flood patterns. In a noteworthy advancement, stakeholders interested in the changing flood patterns of the ... ...

Abstract	With growing concerns over water management in rivers worldwide, researchers are seeking innovative solutions to monitor and understand changing flood patterns. In a noteworthy advancement, stakeholders interested in the changing flood patterns of the Murray Darling Basin (MDB) in Australia, covering an area of 1 million km
Language	English
Publishing date	2023-09-23
Publishing country	England
Document type	Dataset ; Journal Article
ZDB-ID	2775191-0
ISSN	2052-4463 ; 2052-4463
ISSN (online)	2052-4463
ISSN	2052-4463
DOI	10.1038/s41597-023-02559-4
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Article ; Online: Characterisation of meteorological drought at sub-catchment scale in Afghanistan using station-observed climate data.

Yun Chen / David Penton / Fazlul Karim / Santosh Aryal / Shahriar Wahid / Peter Taylor / Susan M Cuddy

PLoS ONE, Vol 18, Iss 2, p e

2023 Volume 0280522

Abstract	Droughts have severely affected Afghanistan over the last four decades, leading to critical food shortages where two-thirds of the country's population are in a food crisis. Long years of conflict have lowered the country's ability to deal with hazards such as drought which can rapidly escalate into disasters. Understanding the spatial and temporal distribution of droughts is needed to be able to respond effectively to disasters and plan for future occurrences. This study used Standardized Precipitation Evapotranspiration Index (SPEI) at monthly, seasonal and annual temporal scales to map the spatiotemporal change dynamics of drought characteristics (distribution, frequency, duration and severity) in Afghanistan. SPEI indices were mapped for river basins, disaggregated into 189 sub-catchments, using monthly precipitation and potential evapotranspiration derived from temperature station observations from 1980 to 2017. The results show these multi-dimensional drought characteristics vary along different years, change among sub-catchments, and differ across temporal scales. During the 38 years, the driest decade and period are 2000s and 1999-2022, respectively. The 2000-01 water year is the driest with the whole country experiencing 'severe' to 'extreme' drought, more than 53% (87 sub-catchments) suffering the worst drought in history, and about 58% (94 sub-catchments) having 'very frequent' drought (7 to 8 months) or 'extremely frequent' drought (9 to 10 months). The estimated seasonal duration and severity present significant variations across the study area and among the study period. The nation also suffers from recurring droughts with varying length and intensity in 2004, 2006, 2008 and most recently 2011. There is a trend towards increasing drought with longer duration and higher severity extending all over sub-catchments from southeast to north and central regions. These datasets and maps help to fill the knowledge gap on detailed sub-catchment scale meteorological drought characteristics in Afghanistan. The ...
Keywords	Medicine ; R ; Science ; Q
Subject code	910
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Amplification of hydrological model uncertainties in projected climate simulations of the Upper Indus Basin: Does it matter where the water is coming from?

Dolk, Michaela / Penton, David J / Ahmad, Mobin D

Hydrological processes. 2020 May 15, v. 34, no. 10

2020

Abstract: There is a growing appreciation of the uncertainties in the estimation of snow‐melt and glacier‐melt as a result of climate change in high elevation catchments. Through a detailed examination of three hydrological models in two catchments, and ... ...

Abstract	There is a growing appreciation of the uncertainties in the estimation of snow‐melt and glacier‐melt as a result of climate change in high elevation catchments. Through a detailed examination of three hydrological models in two catchments, and interpretation of results from previous studies, we observed that many variations in estimated streamflow could be explained by the selection of a best parameter set from the possible good model parameters. The importance of understanding changing glacial dynamics is critically important for our study areas in the Upper Indus Basin where Pakistan's policymakers are planning infrastructure to meet the future energy and water needs of hundreds of millions of people downstream. Yet, the effect of climate on glacial runoff and climate on snowmelt runoff is poorly understood. With the HBV model, for example, we estimated glacial melt as between 56% and 89% for the Hunza catchment. When rainfall was a scaled parameter, the models estimated glacial melt as between 20% and 100% of streamflow. These parameter sets produced wildly different projections of future climate for RCP8.5 scenarios in 2046–2075 compared to 1976–2005. Assuming no glacial shrinkage, for one climate projection, we found that the choice among good parameter sets resulted in projected values of future streamflow across a range from +54% to +125%. Parameter selection was the most significant source of uncertainty in the glaciated catchment and amplified climate model uncertainty, whereas climate model choice was more important in the rainfall dominated catchment. Although the study focuses on Pakistan, the overall conclusions are instructive for other similar regions in the world. We suggest that modellers of glaciated catchments should present results from at least the book‐ends: models with low sensitivity to ice‐melt and models with high sensitivity to ice‐melt. This would reduce confusion among decision makers when they are faced with similar contrasting results.
Keywords	altitude ; basins ; climate ; climate change ; climate models ; energy ; hydrologic models ; infrastructure ; model uncertainty ; people ; rain ; runoff ; shrinkage ; snowmelt ; stream flow ; watersheds ; Pakistan
Language	English
Dates of publication	2020-0515
Size	p. 2200-2218.
Publishing place	John Wiley & Sons, Inc.
Document type	Article
Note	NAL-AP-2-clean ; JOURNAL ARTICLE
ZDB-ID	1479953-4
ISSN	1099-1085 ; 0885-6087
ISSN (online)	1099-1085
ISSN	0885-6087
DOI	10.1002/hyp.13718
Database	NAL-Catalogue (AGRICOLA)

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