Aquaporin-2 in the early stages of the adenine-induced chronic kidney disease model

PLoS ONE, Год журнала: 2025, Номер 20(1), С. e0314827 - e0314827

Опубликована: Янв. 30, 2025

Chronic kidney disease (CKD) is one of the leading health problems in world. It silent early stages and gradually progresses, inducing renal physiological structural alterations. Moreover, CKD associated with impaired life quality, increased risk for cardiovascular diseases, reduced expectancy. Different animal models differ underlying etiology, time onset, diseases. The 0.25% adenine diet induces progressive damage, constituting an adequate model mimicking human CKD. Vasopressin (VP) was postulated as a mediator CKD, mainly acting through its V2 receptors. However, molecular mechanisms involved pathogenesis this condition progression still are not entirely understood. This study aimed to evaluate if AQP2 expression altered adenine-induced rats at development (two weeks) assess potential beneficial effect Tolvaptan (a receptor antagonist) treatment. We showed medullary two weeks administration. increase cytoplasmic, explaining urinary volume suggesting possible non-canonical role AQP2. In addition, effectively inhibited both control rats, decreasing increasing diuresis. slightly BUN plasma creatinine. On other hand, alterations induced by were prevented Tolvaptan.

Язык: Английский

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Isoforskolin, adenylate cyclase agonist, inhibits endothelial-to-mesenchymal transition in atherosclerosis

Phytomedicine, Год журнала: 2025, Номер 139, С. 156520 - 156520

Опубликована: Фев. 16, 2025

Язык: Английский

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Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 9, 2025

Abstract ANO1 plays a crucial role in determining numerous physiological functions, including epithelial secretion, yet its regulatory mechanisms remain incompletely understood. Here, we describe fundamental dynamic regulation of surface expression and Ca 2+ -dependent gating via the cAMP/PKA pathway at STIM1 ER/PM junctions. At these junctions, assembles AC-AKAP-PKA complexes, while E-Syt1 mediates formation ANO1-VAPA-IRBIT-E-Syt1-AC8-AKAP5-PKA complex, that phosphorylates S673, increasing affinity. Within cAMP pathways act synergistically to enhance function. By contrast, E-Syt2 dissociates ANO1-VAPA interaction, forming ANO1-IRBIT-E-Syt2-AC6-AKAP11-PKA complex S221, which markedly reduces The effects E-Syts are primarily mediated by their reciprocal junctional PI(4)P, PI(4,5)P 2 PtdSer. Accordingly, IRBIT deletion mice impairs receptor-stimulated activation fluid secretion. These findings should have broad implications for roles functions across various tissues.

Язык: Английский

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Diesel exhaust particles alter mitochondrial bioenergetics and cAMP producing capacity in human bronchial epithelial cells

Frontiers in Toxicology, Год журнала: 2024, Номер 6

Опубликована: Июль 25, 2024

Air pollution from diesel combustion is linked in part to the generation of exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute a decline lung function. Cyclic AMP (cAMP) signaling critical for homeostasis. The impact on cAMP largely unknown.

Язык: Английский

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Chemical, biochemical, and structural similarities and differences of dermatological cAMP phosphodiesterase-IV inhibitors

Journal of Investigative Dermatology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

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Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Янв. 9, 2025

The expanding field of hematopoietic cell transplantation (HCT) for non-malignant diseases, including those amenable to gene therapy or editing, faces challenges due limited donor availability and the toxicity associated with collection methods. Umbilical cord blood (CB) represents a readily accessible source stem progenitor cells (HSPCs); however, dose obtainable from single unit is frequently insufficient. This limitation can be addressed by enhancing potency HSPCs, specifically their capacity reconstitute hematopoiesis. In our study, we investigated combined effects treprostinil, prostaglandin analog, cinacalcet, calcium-sensing receptor modulator, on reconstitution A Lineage Cell Depletion Kit was employed isolate lineage-negative (lin-) HSPCs mouse bone marrow. Human CB CD34 Positive Selection utilized CD34+ healthy donors. vitro, combination migration, adhesion, differentiation were assessed. vivo, homing engraftment examined. Eight-week-old female male C57BL/6J, BALB/c, NSG mice served as recipient models. When administered concomitantly, treprostinil cinacalcet exhibited mutual antagonism: survival animals lower when both drugs together compared either agent alone. Conversely, sequential regimen involving priming treprostinil/forskolin followed treatment in vivo enhanced survival, irrespective whether hematopoiesis reconstituted human murine HSPCs. vitro assays demonstrated migration adhesion response presence suggesting potential synergistic effects. Colony formation confirmed synergism. Augmenting marrow shows promise rescuing patients undergoing HCT. approach particularly beneficial at high risk transplant failure numbers available Furthermore, has alleviate burden risks HSPC donation, it would reduce number needed collection.

Язык: Английский

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Inhibition of adenylyl cyclase 1 (AC1) and exchange protein directly activated by cAMP (EPAC) restores ATP-sensitive potassium (KATP) channel activity after chronic opioid exposure

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

Abstract Prolonged exposure to Gαi/o receptor agonists such as opioids can lead a sensitization of adenylyl cyclases (ACs), resulting in heterologous or cyclic AMP (cAMP) overshoot. The molecular consequences cAMP overshoot are not well understood, but this adaptive response is suggested play critical role the development opioid tolerance and withdrawal. We found that genetic reduction AC1 simultaneous upregulation ATP-sensitive potassium (K ATP ) channel subunits, SUR1 Kir6.2, significantly attenuated morphine reduced naloxone-precipitated In vitro models utilized an EPAC2-GFP-cAMP biosensor investigate cyclase SH-SY5Y neuroblastoma cells HEKΔAC3/6 knockout cells. Acute application DAMGO decreased signal from biosensor, while chronic administration resulted enhanced production following AC stimulation. Inhibition was observed with naloxone (NAL), pertussis toxin (PTX), neddylation inhibitor, MLN4924 (Pevonedistat), co-expression β-adrenergic kinase C-terminus (βARK-CT). After establishment AC1-EPAC models, we inhibition EPAC activity after treatment, using thallium-based assay Similar data were obtained mouse dorsal root ganglia (DRG) treatment. This study presents evidence for investigating further signaling target withdrawal, by increasing affecting channels downstream receptors. Graphical

Язык: Английский

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Iloprost Concentration‐Dependently Attenuates Platelet Function and Apoptosis by Elevating PKA Activity

Journal of Cellular and Molecular Medicine, Год журнала: 2025, Номер 29(3)

Опубликована: Фев. 1, 2025

ABSTRACT Iloprost, a prostacyclin (PGI 2 ) analogue, stimulates the IP receptor (PTGIR) to interact with Gsα β/γ complex, leading activation of adenylate cyclase, which enzyme produces second messenger cAMP. Elevation in cAMP triggers intracellular signalling events and regulates wide variety cellular activities. Thus, we evaluated effects Iloprost on platelet function apoptosis vivo haemostasis thrombosis, as well underlying mechanisms. Firstly, showed that concentration‐dependently inhibited agonist‐induced P‐selectin exposure, integrin αIIbβ3 activation, aggregation, ATP release, spreading, clot retraction. Moreover, dose‐dependently FeCl 3 ‐induced mouse mesenteric arteriole thrombosis markedly prolonged tail bleeding time. also mitochondrial membrane potential (ΔΨm) depolarisation phosphatidylserine (PS) externalisation platelets, thereby inhibiting apoptosis, at concentrations lower than nM only but not function. Importantly, low doses elevated peripheral counts GPIbα antibody‐induced immune thrombocytopenia (ITP). Mechanistic studies antagonised decline protein kinase A (PKA) activity elevation cytoplasmic Ca 2+ attenuating aggregation. PKA dephosphorylation proapoptotic BAD reduced caspase‐3 activity, thus retarding apoptosis. These data demonstrate inhibits by elevating activity. Moderate‐dose impairs via suppression function, low‐dose elevates levels while having no

Язык: Английский

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A signal transduction blind spot: the function of adenylyl cyclase transmembrane domains

FEBS Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

Signal transduction of external primary signals into intracellular elevations the second messenger cyclic AMP is an ancient and universal regulatory mechanism in biology. In mammals, 9 10 adenylyl cyclases (ACs) share a common topology that includes large transmembrane (TM) domain assembled from two clusters six helices. This accounts for ~ 35% coding sequence but, remarkably, its function still open question. this viewpoint, we consider how first AC sequences spurred ideas purpose TM domains, including voltage‐sensing transporter functions. original conceptions signalling, ACs were put forward as potential receptors, discuss emerging evidence support function. We also growing cyclase helical bundles help to organise multiprotein signalling complexes by engaging interactions with other membrane‐embedded proteins. Cyclase regions are more diverse between isoforms than catalytic domain—we conclude considering might be exploited therapeutic strategies targeting specific isoforms.

Язык: Английский

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Vascular actions of Ang 1-7 and Ang 1-8 through EDRFs and EDHFs in non-diabetes and diabetes mellitus

Nitric Oxide, Год журнала: 2025, Номер 156, С. 9 - 26

Опубликована: Март 1, 2025

Язык: Английский

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