scholarly journals α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheng-Hsuan Ho ◽  
Hsiu-Hui Yang ◽  
Shih-Han Su ◽  
Ai-Hsin Yeh ◽  
Ming-Jiun Yu
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Nuclear Translocation ◽  
Collecting Duct ◽  
Apical Plasma Membrane ◽  
Membrane Insertion ◽  
Short Term ◽  
Aquaporin 2 ◽  
Mrna And Protein Expression

Water permeability of the kidney collecting ducts is regulated by the peptide hormone vasopressin. Between minutes and hours (short-term), vasopressin induces trafficking of the water channel protein aquaporin-2 to the apical plasma membrane of the collecting duct principal cells to increase water permeability. Between hours and days (long-term), vasopressin induces aquaporin-2 gene expression. Here, we investigated the mechanisms that bridge the short-term and long-term vasopressin-mediated aquaporin-2 regulation by α-actinin 4, an F-actin crosslinking protein and a transcription co-activator of the glucocorticoid receptor. Vasopressin induced F-actin depolymerization and α-actinin 4 nuclear translocation in the mpkCCD collecting duct cell model. Co-immunoprecipitation followed by immunoblotting showed increased interaction between α-actinin 4 and glucocorticoid receptor in response to vasopressin. ChIP-PCR showed results consistent with α-actinin 4 and glucocorticoid receptor binding to the aquaporin-2 promoter. α-actinin 4 knockdown reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. α-actinin 4 knockdown did not affect vasopressin-induced glucocorticoid receptor nuclear translocation, suggesting independent mechanisms of vasopressin-induced nuclear translocation of α-actinin 4 and glucocorticoid receptor. Glucocorticoid receptor knockdown profoundly reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. In the absence of glucocorticoid analog dexamethasone, vasopressin-induced increases in glucocorticoid receptor nuclear translocation and aquaporin-2 mRNA were greatly reduced. α-actinin 4 knockdown further reduced vasopressin-induced increase in aquaporin-2 mRNA in the absence of dexamethasone. We conclude that glucocorticoid receptor plays a major role in vasopressin-induced aquaporin-2 gene expression that can be enhanced by α-actinin 4. In the absence of vasopressin, α-actinin 4 crosslinks F-actin underneath the apical plasma membrane, impeding aquaporin-2 membrane insertion. Vasopressin-induced F-actin depolymerization in one hand facilitates aquaporin-2 apical membrane insertion and in the other hand frees α-actinin 4 to enter the nucleus where it binds glucocorticoid receptor to enhance aquaporin-2 gene expression.

Axial heterogeneity in basolateral AQP2 localization in rat kidney: effect of vasopressin

2003 ◽  
Vol 284 (4) ◽  
pp. F701-F717 ◽  
Author(s):  
Birgitte Mønster Christensen ◽  
Weidong Wang ◽  
Jørgen Frøkiær ◽  
Søren Nielsen
Keyword(s):  
Plasma Membrane ◽  
Receptor Antagonist ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Apical Plasma Membrane ◽  
Brattleboro Rats ◽  
Short Term ◽  
Principal Cells ◽  
Medullary Collecting Duct

The purpose of the present study was to examine whether there is axial heterogeneity in the basolateral plasma membrane (BLM) localization of AQP2 and whether altered vasopressin action or medullary tonicity affects the BLM localization of AQP2. Immunocytochemistry and immunoelectron microscopy revealed AQP2 labeling of the BLM in connecting tubule (CNT) cells and inner medullary collecting duct (IMCD) principal cells in normal rats and vasopressin-deficient Brattleboro rats. In contrast there was little basolateral AQP2 labeling in cortical (CCD) and outer medullary collecting duct principal cells. Short-term desamino-Cys1, D-Arg8 vasopressin (dDAVP) treatment (2 h) of Brattleboro rats caused no increase in AQP2 labeling of the BLM. In contrast, long-term dDAVP treatment (6 days) of Brattleboro rats caused an increased BLM labeling in CNT, CCD, and IMCD. Treatment of normal rats with V2-receptor antagonist for 60 min caused retrieval of AQP2 from the apical plasma membrane. Moreover, AQP2 labeling of the BLM was unchanged in CNT and IMCD but increased in CCD. In conclusion, there is an axial heterogeneity in the subcellular localization of AQP2 with prominent AQP2 labeling of the BLM in CNT and IMCD. There was no increase in AQP2 labeling of the BLM in response to short-term dDAVP. Moreover, acute V2-receptor antagonist treatment did not cause retrieval of AQP2 from the BLM. In contrast, long-term dDAVP treatment caused a major increase in AQP2 expression in the BLM in CCD.

scholarly journals Mechanisms of short-term and long-term adaptation

2020 ◽  
pp. 77-86
Author(s):  
Н.Б. Панкова
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Adaptive Response ◽  
Educational Environment ◽  
Stress Factors ◽  
Short Term ◽  
Functional Reserve ◽  
Short Term Adaptation ◽  
Expression Program

В лекции рассмотрены общие представления об адаптации, основанные на классических работах Г. Селье, Ф.З. Меерсона, Н.А. Агаджаняна, а также особенности адаптивного ответа развивающегося организма. Рассмотрены механизмы срочной адаптации как мобилизации функциональных резервов организма. В качестве одного из механизмов долговременной адаптации представлена эпигенетическая регуляция, которая позволяет выбрать и реализовать программу экспрессии генов - в соответствии с этапом онтогенетического развития, или средовым окружением. В качестве ещё одного механизма долговременной адаптации рассмотрено воздействие на генетический материал. Приведены примеры формирования адаптивного ответа организма на физико-химические и климатогеографические стрессорные факторы. Отдельно проанализированы механизмы адаптивного ответа организма детей на факторы образовательной среды. The lecture addresses general ideas about adaptation based on classic studies by H. Selye, F.Z. Meerson, and N.A. Agadzhanyan and features of the adaptive response in a developing body. Mobilization of the functional reserve is considered as a mechanism of short-term adaptation. Epigenetic regulation is presented as one of mechanisms for long-term adaptation, which allows selecting and implementing a gene expression program consistent with the stage of ontogenetic development or the environment. Another mechanism of long-term adaptation is influence on the genome. The lecture provides examples of adaptation to physicochemical and climatic geographical stress factors. Mechanisms of the adaptive response to factors of the educational environment in children are analyzed separately.

Abstract 9411: Urine Aquaporin-2 Level is a Novel Marker for the Better Prognosis After Long-Term Tolvaptan Treatment in Patients With Advanced Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Teruhiko Imamura ◽  
Koichiro Kinugawa ◽  
Takeo Fujino ◽  
Toshiro Inaba ◽  
Hisataka Maki ◽  
...  
Keyword(s):  
Heart Failure ◽  
De Novo ◽  
Collecting Duct ◽  
Initial Response ◽  
Aquaporin 2 ◽  
Long Term Treatment ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Introduction: Preserved function of collecting duct is essential for the response to tolvaptan (TLV), and urinary level of aquaporin 2 (U-AQP2) can be a marker for vasopressin-dependent activity of collecting duct. Hypothesis: Higher levels of U-AQP2 in proportion to plasma levels of vasopressin (P-AVP) may be associated with better initial responses to TLV and eventually result in the improved prognosis after long-term treatment of TLV. Methods: Consecutive 60 in-hospital patients with stage D heart failure (HF) who received TLV on a de novo basis were enrolled during 2011-2013. We also selected 60 HF patients by propensity score matching who were hospitalized during the same period but never treated with TLV. Events were defined as death and/or HF re-hospitalization. Results: TLV (3.75-15 mg/day) was continuously administered except death or ventricular assist device implantation occurred. There were 41 patients (group 1) who had increases in UV over the first 24 h after TLV initiation, and all of them had U-AQP2/P-AVP ≥0.5 х103 with higher U-AQP2 levels (5.42 ± 3.54 ng/mL) before TLV treatment. On the other hand, UV rather decreased even after TLV initiation in 19 patients over the first 24 h (group 2). Those in the group 2 universally had U-AQP2/P-AVP <0.5 х103, extremely low U-AQP2 levels (0.76 ± 0.59 ng/mL, p<0.001 vs. group 1), and similar P-AVP with the group 1 at baseline. The 41 and 19 patients without TLV treatment (group 3 and 4) were respectively matched to the group 1 and 2 by propensity scores. Interestingly, every patient in the group 3 had U-AQP2/P-AVP ≥0.5 х103, and vice versa in the group 4. Among the four groups, congestion-related symptoms were only improved in the group 1 after 1 month of enrollment. The patients in the group 1 had significantly better event-free survival over 2-year by TLV treatment compared with the group 3 (76% vs. 43%, p<0.014). In contrast, the patients in the group 2 and 4 had very poor prognoses regardless of TLV treatment (7% vs. 11%, p=0.823). Conclusions: U-AQP2/P-AVP is a novel predictor for the initial response to TLV in HF patients. Patients with higher U-AQP2/P-AVP may enjoy a better prognosis by long-term TLV treatment probably due to efficient resolution of congestion.

scholarly journals Developmental conditions modulate DNA methylation at the glucocorticoid receptor gene with cascading effects on expression and corticosterone levels in zebra finches

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Blanca Jimeno ◽  
Michaela Hau ◽  
Elena Gómez-Díaz ◽  
Simon Verhulst
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Early Life ◽  
Receptor Gene ◽  
Regulatory Region ◽  
Long Term Effects ◽  
Glucocorticoid Receptor Gene ◽  
Developmental Conditions

Abstract Developmental conditions can impact the adult phenotype via epigenetic changes that modulate gene expression. In mammals, methylation of the glucocorticoid receptor gene Nr3c1 has been implicated as mediator of long-term effects of developmental conditions, but this evidence is limited to humans and rodents, and few studies have simultaneously tested for associations between DNA methylation, gene expression and phenotype. Adverse environmental conditions during early life (large natal brood size) or adulthood (high foraging costs) exert multiple long-term phenotypic effects in zebra finches, and we here test for effects of these manipulations on DNA methylation and expression of the Nr3c1 gene in blood. Having been reared in a large brood induced higher DNA methylation of the Nr3c1 regulatory region in adulthood, and this effect persisted over years. Nr3c1 expression was negatively correlated with methylation at 2 out of 8 CpG sites, and was lower in hard foraging conditions, despite foraging conditions having no effect on Nr3c1 methylation at our target region. Nr3c1 expression also correlated with glucocorticoid traits: higher expression level was associated with lower plasma baseline corticosterone concentrations and enhanced corticosterone reactivity. Our results suggest that methylation of the Nr3c1 regulatory region can contribute to the mechanisms underlying the emergence of long-term effects of developmental conditions in birds, but in our system current adversity dominated over early life experiences with respect to receptor expression.

Advances in aquaporin-2 trafficking mechanisms and their implications for treatment of water balance disorders

2020 ◽  
Vol 319 (1) ◽  
pp. C1-C10 ◽  
Author(s):  
Robert A. Fenton ◽  
Sathish K. Murali ◽  
Hanne B. Moeller
Keyword(s):  
Protein Interactions ◽  
Collecting Duct ◽  
Water Channel ◽  
Plasma Osmolality ◽  
Carboxyl Terminus ◽  
Apical Plasma Membrane ◽  
Tail Domain ◽  
Water Reabsorption ◽  
Aquaporin 2

In mammals, conservation of body water is critical for survival and is dependent on the kidneys’ ability to minimize water loss in the urine during periods of water deprivation. The collecting duct water channel aquaporin-2 (AQP2) plays an essential role in this homeostatic response by facilitating water reabsorption along osmotic gradients. The ability to increase the levels of AQP2 in the apical plasma membrane following an increase in plasma osmolality is a rate-limiting step in water reabsorption, a process that is tightly regulated by the antidiuretic hormone arginine vasopressin (AVP). In this review, the focus is on the role of the carboxyl-terminus of AQP2 as a key regulatory point for AQP2 trafficking. We provide an overview of AQP2 structure, disease-causing mutations in the AQP2 carboxyl-terminus, the role of posttranslational modifications such as phosphorylation and ubiquitylation in the tail domain, and their implications for balanced trafficking of AQP2. Finally, we discuss how various modifications of the AQP2 tail facilitate selective protein-protein interactions that modulate the AQP2 trafficking mechanism.

scholarly journals The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor

2019 ◽  
Vol 105 (3) ◽  
pp. 716-734 ◽  
Author(s):  
Benjamin Small ◽  
Charles E F Millard ◽  
Edwina P Kisanga ◽  
Andreanna Burman ◽  
Anika Anam ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Uterine Fibroid ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Ex Vivo ◽  
Therapeutic Option ◽  
The Body ◽  
Dependent Manner ◽  
Ulipristal Acetate

Abstract Context The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. Objective To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. Design Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. Results Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. Conclusions These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.

Dynamics of aquaporin-2 serine-261 phosphorylation in response to short-term vasopressin treatment in collecting duct

2007 ◽  
Vol 292 (2) ◽  
pp. F691-F700 ◽  
Author(s):  
Jason D. Hoffert ◽  
Jakob Nielsen ◽  
Ming-Jiun Yu ◽  
Trairak Pisitkun ◽  
Stephen M. Schleicher ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Phosphorylation Site ◽  
Water Channel ◽  
Distal Tubule ◽  
Immunohistochemical Analysis ◽  
Immunoblot Analysis ◽  
Dot Blot ◽  
Short Term ◽  
Antibody Recognition ◽  
Aquaporin 2

We recently identified a novel phosphorylation site, serine-261 (pS261), in the COOH-terminus of the vasopressin-regulated water channel, aquaporin-2 (AQP2). To address whether phosphorylation at this site is regulated by vasopressin, a rabbit polyclonal phospho-specific antibody was generated. Dot blot and immunoblot analysis demonstrated that this antibody specifically recognizes AQP2 phosphorylated at pS261, and that phosphorylation of S256 (pS256), a site already known to be regulated by vasopressin, does not interfere with antibody recognition. Immunohistochemical analysis revealed intense pS261 labeling of inner medullary collecting duct (IMCD) from wild-type mice, while sections from AQP2 knockout animals showed a general absence of labeling. AQP2 pS261 was present in principal cells of all mouse and rat distal tubule segments from the connecting tubule to the terminal IMCD. Co-immunolabeling of collecting duct with phospho-specific and total AQP2 antibodies revealed that pS261 and pS256 have distinct subcellular distributions. Levels of pS256 increased, while the amount of pS261 significantly decreased in freshly isolated rat IMCD samples incubated with 1 nM [deamino-Cys1,d-Arg8]vasopressin for 30 min. Similarly, based on immunohistochemical labeling, the amount of pS261 was reduced in all collecting duct segments of Brattleboro rats treated with [deamino-Cys1,d-Arg8]vasopressin for 2 h. This study reveals a reciprocal change in S256 and S261 phosphorylation in response to short-term vasopressin exposure, suggesting that these residues may serve distinct roles in regulation of AQP2 subcellular distribution and collecting duct water permeability.

scholarly journals Regulation of pituitary inhibin/activin subunits and follistatin gene expression by GnRH in female rats

2011 ◽  
Vol 210 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Petra Popovics ◽  
Zoltan Rekasi ◽  
Alan J Stewart ◽  
Magdolna Kovacs
Keyword(s):  
Gene Expression ◽  
Mrna Level ◽  
Inhibin B ◽  
Female Rats ◽  
Pituitary Cells ◽  
Mrna Levels ◽  
Short Term ◽  
Α Subunit ◽  
Long Term Treatment

Pituitary inhibin B, activin B, and follistatin are local regulators of FSH. Activin B is a homodimeric molecule (βB–βB), while inhibin B contains an α and a βB subunit. The regulation of gene expression of α, βB, and follistatin by local and endocrine hormones was examined in pituitaries from female rats and in perifused pituitary cells by RT-PCR. Ovariectomy (OVX) induced an elevation in the mRNA level of α and βB subunits and follistatin. Short-term (4 h) treatment of pituitary cells with GnRH decreased both the inhibin α and the inhibin/activin βB subunit mRNA levels, while long-term treatment (20 h) with 100 nM GnRH stimulated the expression of both subunits. In contrast, the mRNA level of follistatin was elevated after the short-term GnRH treatment. Long-term exposure of pituitary cells to estradiol and inhibin B suppressed the mRNA expression of βB and had no effect on the expression of α subunit and follistatin. Our results demonstrate that the increased expressions of inhibin/activin subunits and follistatin in the post-OVX period can be induced by the lack of gonadal negative feedback, resulting in a high GnRH environment in the pituitary. This study reports for the first time that GnRH administered in high doses and for a long period stimulates the gene expression of inhibin/activin subunits and thereby may contribute to the stimulatory effect of OVX on the expression of these genes.

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