Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells

Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic–pituitary–adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.

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Regulation of Angiotensin Type 2 Receptor in Bovine Granulosa Cells

Endocrinology ◽

10.1210/en.2007-1767 ◽

2008 ◽

Vol 149 (10) ◽

pp. 5004-5011 ◽

Cited By ~ 20

Author(s):

Valério M. Portela ◽

Paulo B. D. Gonçalves ◽

Angela M. Veiga ◽

Edmir Nicola ◽

José Buratini ◽

...

Keyword(s):

Granulosa Cells ◽

Theca Cells ◽

Protein Levels ◽

Estradiol Secretion ◽

Morphogenetic Protein ◽

Angiotensin Type 2 Receptor ◽

Igf I ◽

Follicle Atresia

Angiotensin II (AngII) is best known for its role in blood pressure regulation, but it also has documented actions in the reproductive system. There are two AngII receptors, type 1 (AGTR1) and type 2 (AGTR2). AGTR2 mediates the noncardiovascular effects of AngII and is expressed in the granulosa cell layer in rodents and is associated with follicle atresia. In contrast, expression of AGTR2 is reported to occur only in theca cells in cattle. The objective of the present study was to determine whether AngII also plays a role in follicle atresia in cattle. RT-PCR demonstrated AGTR2 mRNA in both granulosa and theca cells of bovine follicles. The presence of AGTR2 protein was confirmed by immunofluorescence. Abundance of AGTR2 mRNA in granulosa cells was higher in healthy compared with atretic follicles, whereas in theca cells, it did not change. Granulosa cells were cultured in serum-free medium, and treatment with hormones that increase estradiol secretion (FSH, IGF-I, and bone morphogenetic protein-7) increased AGTR2 mRNA and protein levels, whereas fibroblast growth factors inhibited estradiol secretion and AGTR2 protein levels. The addition of AngII or an AGTR2-specific agonist to granulosa cells in culture did not affect estradiol secretion or cell proliferation but inhibited abundance of mRNA encoding serine protease inhibitor E2, a protein involved in tissue remodeling. Because estradiol secretion is a major marker of nonatretic granulosa cells, these data suggest that AngII is not associated with follicle atresia in cattle but may have other specific roles during follicle growth.

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Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

Nature Communications ◽

10.1038/s41467-021-25248-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Christopher Agnew ◽

Pelin Ayaz ◽

Risa Kashima ◽

Hanna S. Loving ◽

Prajakta Ghatpande ◽

...

Keyword(s):

Md Simulations ◽

Kinase Domain ◽

Structural Basis ◽

Type I ◽

Type Ii ◽

Exchange Mass Spectrometry ◽

Receptor Complexes ◽

Bmp Receptors ◽

Morphogenetic Protein ◽

Smad Proteins

AbstractUpon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

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Heart involvement in type 1 and type 2 myotonic dystrophy. Insights from a 10-year follow-up study

European Heart Journal ◽

10.1093/ehjci/ehaa946.3145 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

F Fioravanti ◽

P.G Golzio ◽

M.L Carbone ◽

A Panarelli ◽

M Gagliardi ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Cardiac Involvement ◽

Type I ◽

Device Therapy ◽

Cardiac Symptom ◽

Conduction Disorders ◽

Reliable Marker

Abstract Background and aim Myotonic Dystrophy (MD) is the most common inherited muscular dystrophy of the adult. Cardiac manifestation, including arrhythmias and conduction disorders, contributes significantly to the morbidity and mortality of the disease. The transition from a subclinical form of cardiac involvement to potentially life-threating manifestations is highly variable and not yet entirely understood. Aim of this work is to evaluate whether PQ interval (PQi) prolongation could be a reliable marker to predict left and right ventricle impairment and the necessity of a stricter monitoring. Methods In this retrospective cohort study, we selected all consecutive patients with a confirmed diagnosis of MD (type 1 and type 2) referred to our Centre. We performed clinical, laboratoristic and instrumental assessments (every 3, 6 or 12 months), tailored on each patient's features. Every patient was treated according to the latest guidelines for pharmacological and device therapy. ECG (recorded at 25 and 50 mm/sec), 24h ECG Holter and transthoracic echocardiography were performed at least yearly. Cardiac Magnetic Resonance was requested to better stratify intermediate risk patients to implantable device therapy. Results A total of 72 patients (age 48±15 years, 39% female) were included in the analysis. Patients with MD type 1 and type 2 were referred to our Centre after a mean period of 12 years (SD ±8 years) from initial diagnosis. After a mean follow-up of 5 years (±4 years), 8 patients died (mean age at death: 60±12.4 years), all of them for respiratory insufficiency. We evaluated PQ interval (PQi) evolution and type I AVB onset. No statistically significant differences emerged when stratifying for type I AVB. Nevertheless, a PQi increase of more than 20 ms during the follow-up (even if PQ <200 ms) is significantly associated with lower values of TAPSE and greater LVEDD, while no differences emerged for LVEF, dyastolic function and other echocardiographic parameters. Moreover, the evolution of PQ interval is associated with an increasing number of supraventricular arrhythmias and a worse prognosis (shorter interval from first cardiac symptom to death, p 0.025), despite optimal medical therapy. Conclusions Although relatively rare, MD is a challenge for present Cardiologists. How and when to treat those patients is not codified in guidelines or consensus papers. This study suggests PQi variation as a proxy for critical evolution of MD cardiac involvement. ECG and its modification during lifetime seem pivotal for these patients' care, qualifying as a red flag for stringent follow-up. Further evidences, on larger cohorts, are needed to validate these findings. Funding Acknowledgement Type of funding source: None

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Hepatorenal Syndrome

10.5772/intechopen.97698 ◽

2021 ◽

Author(s):

Arshpal Gill ◽

Ra’ed Nassar ◽

Ruby Sangha ◽

Mohammed Abureesh ◽

Dhineshreddy Gurala ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Failure ◽

Blood Flow ◽

Mortality Rate ◽

Kidney Injury ◽

Type I ◽

Tubular Necrosis ◽

Cirrhotic Patients

Hepatorenal Syndrome (HRS) is an important condition for clinicians to be aware of in the presence of cirrhosis. In simple terms, HRS is defined as a relative rise in creatinine and relative drop in serum glomerular filtration rate (GFR) alongside renal plasma flow (RPF) in the absence of other competing etiologies of acute kidney injury (AKI) in patients with hepatic cirrhosis. It represents the end stage complication of decompensated cirrhosis in the presence of severe portal hypertension, in the absence of prerenal azotemia, acute tubular necrosis or others. It is a diagnosis of exclusion. The recognition of HRS is of paramount importance for clinicians as it carries a high mortality rate and is an indication for transplantation. Recent advances in understanding the pathophysiology of the disease improved treatment approaches, but the overall prognosis remains poor, with Type I HRS having an average survival under 2 weeks. Generally speaking, AKI and renal failure in cirrhotic patients carry a very high mortality rate, with up to 60% mortality rate for patients with renal failure and cirrhosis and 86.6% of overall mortality rates of patients admitted to the intensive care unit. Of the various etiologies of renal failure in cirrhosis, HRS carries a poor prognosis among cirrhotic patients with acute kidney injury. HRS continues to pose a diagnostic challenge. AKI can be either pre-renal, intrarenal or postrenal. Prerenal causes include hypovolemia, infection, use of vasodilators and functional due to decreased blood flow to the kidney, intra-renal such as glomerulopathy, acute tubular necrosis and post-renal such as obstruction. Patients with cirrhosis are susceptible to developing renal impairment. HRS may be classified as Type 1 or rapidly progressive disease, and Type 2 or slowly progressive disease. There are other types of HRS, but this chapter will focus on Type 1 HRS and Type 2 HRS. HRS is considered a functional etiology of acute kidney injury as there is an apparent lack of nephrological parenchymal damage. It is one several possibilities for acute kidney injury in patients with both acute and chronic liver disease. Acute kidney injury (AKI) is one of the most severe complications that could occur with cirrhosis. Up to 50% of hospitalized patients with cirrhosis can suffer from acute kidney injury, and as mentioned earlier an AKI in the presence of cirrhosis in a hospitalized patient has been associated with nearly a 3.5-fold increase in mortality. The definition of HRS will be discussed in this chapter, but it is characterized specifically as a form of acute kidney injury that occurs in patients with advanced liver cirrhosis which results in a reduction in renal blood flow, unresponsive to fluids this occurs in the setting of portal hypertension and splanchnic vasodilation. This chapter will discuss the incidence of HRS, recognizing HRS, focusing mainly on HRS Type I and Type II, recognizing competing etiologies of renal impairment in cirrhotic patients, and the management HRS.

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Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation

Journal of Cell Science ◽

10.1242/jcs.112.20.3519 ◽

1999 ◽

Vol 112 (20) ◽

pp. 3519-3527 ◽

Cited By ~ 10

Author(s):

T. Ebisawa ◽

K. Tada ◽

I. Kitajima ◽

K. Tojo ◽

T.K. Sampath ◽

...

Keyword(s):

Bone Morphogenetic Protein ◽

Osteoblast Differentiation ◽

Transforming Growth Factor ◽

C2c12 Cells ◽

Nuclear Accumulation ◽

Type I ◽

Type Ii ◽

Weakly Bound ◽

Bmp Receptors ◽

Morphogenetic Protein

Bone morphogenetic protein (BMP)-6 is a member of the transforming growth factor (TGF)-(β) superfamily, and is most similar to BMP-5, osteogenic protein (OP)-1/BMP-7, and OP-2/BMP-8. In the present study, we characterized the endogenous BMP-6 signaling pathway during osteoblast differentiation. BMP-6 strongly induced alkaline phosphatase (ALP) activity in cells of osteoblast lineage, including C2C12 cells, MC3T3-E1 cells, and ROB-C26 cells. The profile of binding of BMP-6 to type I and type II receptors was similar to that of OP-1/BMP-7 in C2C12 cells and MC3T3-E1 cells; BMP-6 strongly bound to activin receptor-like kinase (ALK)-2 (also termed ActR-I), together with type II receptors, i.e. BMP type II receptor (BMPR-II) and activin type II receptor (ActR-II). In addition, BMP-6 weakly bound to BMPR-IA (ALK-3), to which BMP-2 also bound. In contrast, binding of BMP-6 to BMPR-IB (ALK-6), and less efficiently to ALK-2 and BMPR-IA, together with BMPR-II was detected in ROB-C26 cells. Intracellular signalling was further studied using C2C12 and MC3T3-E1 cells. Among the receptor-regulated Smads activated by BMP receptors, BMP-6 strongly induced phosphorylation and nuclear accumulation of Smad5, and less efficiently those of Smad1. However, Smad8 was constitutively phosphorylated, and no further phosphorylation or nuclear accumulation of Smad8 by BMP-6 was observed. These findings indicate that in the process of differentiation to osteoblasts, BMP-6 binds to ALK-2 as well as other type I receptors, and transduces signals mainly through Smad5 and possibly through Smad1.

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THE EFFECT OF INGESTION OF HYPERTONIC SALINE ON THE MELANOCYTE-STIMULATING HORMONE CONTENT AND HISTOLOGY OF THE PARS INTERMEDIA OF THE RAT PITUITARY GLAND

Journal of Endocrinology ◽

10.1677/joe.0.0460201 ◽

1970 ◽

Vol 46 (2) ◽

pp. 201-NP ◽

Cited By ~ 27

Author(s):

A. HOWE ◽

A. J. THODY

Keyword(s):

Control Level ◽

Pars Intermedia ◽

Type I ◽

Melanocyte Stimulating Hormone ◽

Level Of Activity ◽

Numerous Type ◽

Rat Pituitary ◽

Stimulating Hormone

SUMMARY The changes in the content of melanocyte-stimulating hormone (MSH) and histology of the neuro-intermediate (n.i.) lobe were followed in rats which drank 2% sodium chloride for periods from 1–15 days. The pars intermedia showed a biphasic response. During the initial phase of 1–4 days there was a rapid rise in the MSH content, by 153% in the first day, falling back to control level by 4 days. These fluctuations were paralleled by an increase in the normally small numbers of Type 2 cells and at the same time numerous Type I cells showed hypertrophy and degranulation. After 4 days on saline there was a second rise in the MSH content, which was still evident at 15 days; during this second period the number of Type 2 cells declined to normal levels. The degranulated Type 1 cells also disappeared, most of Type 1 being smaller in size and intensely PAS-positive. After the ingestion of saline it apparently takes several days before the pars intermedia adapts to a new level of activity. The likely significance of these changes and the possibility of a relationship between the pars intermedia and the neurohypophysis are discussed.

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Regulation of the ALK1 ligands, BMP9 and BMP10

Biochemical Society Transactions ◽

10.1042/bst20160083 ◽

2016 ◽

Vol 44 (4) ◽

pp. 1135-1141 ◽

Cited By ~ 19

Author(s):

Wei Li ◽

Richard M. Salmon ◽

He Jiang ◽

Nicholas W. Morrell

Keyword(s):

Vascular Endothelial Cells ◽

Type I ◽

Hereditary Haemorrhagic Telangiectasia ◽

Essential Information ◽

Affinity Ligands ◽

Protein Levels ◽

Phase Ii Clinical Trials ◽

Morphogenetic Protein ◽

Genes Encoding ◽

Pulmonary Arterial

Bone morphogenetic protein (BMP)9 and BMP10 are high affinity ligands for activin receptor-like kinase 1 (ALK1), a type I BMP receptor mainly expressed on vascular endothelial cells (ECs). ALK1-mediated BMP9/BMP10 signalling pathways have emerged as essential in EC biology and in angiogenesis. Several genetic mutations in the genes encoding the ligands and receptors of this pathway have been reported in two cardiovascular diseases, pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). Administration of recombinant BMP9 reverses experimental PAH in preclinical rodent models. Dalantercept, an Fc-fusion protein of the extracellular domain of ALK1 and a ligand trap for BMP9 and BMP10, is in phase II clinical trials for anti-tumour angiogenesis. Understanding the regulation of BMP9 and BMP10, at both gene and protein levels, under physiological and pathological conditions, will reveal essential information and potential novel prognostic markers for the BMP9/BMP10-targeted therapies.

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Limitations of Current Plasma VonWillebrand Factor (VWF) Activity Tests: A Comprehensive Comparison of Five VWF Activity Assays.

Blood ◽

10.1182/blood.v112.11.3376.3376 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3376-3376

Author(s):

Dong Chen ◽

Rajiv Pruthi ◽

William L. Nichols ◽

John A. Heit

Keyword(s):

Activity Ratio ◽

Light Transmission ◽

Von Willebrand Disease ◽

Assay Method ◽

Type I ◽

Platelet Activity ◽

Platelet Aggregometry ◽

Von Willebrand

Abstract Accurate measurement of plasma von Willebrand factor (VWF) activity is essential for the laboratory diagnosis and treatment monitoring of von Willebrand disease (VWD). Currently available VWF activity assays include VWF ristocetin cofactor activity by manual light transmission platelet aggregometry (VWF:RCo–Agg) or flow cytometry (VWF:RCo–FL), collagen I and III binding activity (VWF:Co–I and –III) (Technozym), and platelet activity by latex agglutination (VWF:Lx) (Instrumental Laboratory). In this study we evaluated and compared the accuracy and precision of these 5 assay methods. Plasma samples from 11 normal donors and 41 patients categorized as type 1 (n=20) or type 2 (n=21) VWD based on clinical evaluation, fVIII:C activity, VWF:RCo–Agg, VWF antigen (VWF:Ag) level and plasma VWF multimer analysis by agarose gel electrophoresis were assayed for VWF activity by VWF:RCo–FL, VWF:Co–I, VWF:Co–III and VWF:Lx methods. The VWF:Ag/VWF activity ratio by VWF activity assay method was calculated for each sample. For normal donors and type I VWD patients, VWF:RCo–FL and VWF:Lx correlated well with VWF:RCo–Agg (R2=0.87, and 0.97, respectively), while VWF:Co–I and –III were lower compared to VWF:RCo-Agg. For type 2 VWD patients, different VWF:Ag/VWF activity ratio cutoffs (range 0.3–0.7) were used (Figure). Both VWF:RCo–Agg and –FL were sensitive (95%) and specific (97%) for type 2 VWD while the VWF:Lx was slightly less sensitive (81%) but was very specific (100%). VWF:Co–I and –III were the least sensitive (<90%) and specific (<90%); both methods had high false positive and negative rates for type 2 VWD. In Summary, for normals and type 1 VWD patients, VWF:RCo–FL and VWF:Lx correlate well with VWF:RCo–Agg and have similar sensitivities and specificities for type 2 VWD. VWF:Co–I and –III are unreliable for assessing plasma VWF activity.

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VWF Binding to Types I, III or VI Collagen In the ZPMCB-VWD with Identification of Subjects with Selective Reduced Plasma VWF:CB

Blood ◽

10.1182/blood.v116.21.235.235 ◽

2010 ◽

Vol 116 (21) ◽

pp. 235-235

Author(s):

Veronica H Flood ◽

Sandra L Haberichter ◽

Kenneth D Friedman ◽

Steven R Lentz ◽

Joan Cox Gill ◽

...

Keyword(s):

Amino Acid ◽

Type I ◽

Healthy Controls ◽

Type Vi Collagen ◽

Collagen Binding ◽

Type Iii ◽

Type 3 ◽

Von Willebrand

Abstract 235 Von Willebrand Disease (VWD) is a common bleeding disorder caused by quantitative (types 1 and 3) and qualitative (type 2) abnormalities in von Willebrand factor (VWF). Defective VWF binding to collagen (VWF:CB) has been identified in VWD patients, but the type(s) and amount of collagen vary between recommended assays. We measured VWF:CB using separate assays for types I, III, and VI collagen in plasmas from 233 healthy controls and 315 VWD index cases (261 type 1, 37 type 2 and 17 type 3) recruited into the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCB-VWD). Additional studies included VWF antigen (Ag), VWF ristocetin-cofactor (RCo), VWF multimer, and VWF gene sequence analysis. VWF:CB was tested using ELISA assays with type I human placental collagen (5 ug/ml), type III human placental collagen (1 ug/ml), and by a commercial human placental type VI VWF:CB assay (Technoclone, Austria). Normal ranges were established for VWF:CB and VWF:CB/Ag ratios with the ZPMCB-VWD healthy control population. Three subjects (2 healthy controls and 1 type 1 VWD subject) were identified with reduced VWF:CB and reduced VWF:CB/Ag ratios to type VI collagen, despite normal results with type I and type III collagen. The two control subjects had VWF:CB/Ag ratios of 0.43 and 0.51 for type VI collagen. The patient with type 1 VWD had absent type VI VWF:CB and a VWF:Ag of 54 IU/dL with a history of clinical epistaxis and an EU Bleeding Score of 8 (normal less than or equal to 3). VWF sequencing demonstrated that these three individuals had an A1 loop polymorphism, R1399H, which has been previously reported as a VWF polymorphism. No other individuals in our study had this sequence change. Of particular note was that the VWF:CB/Ag ratios for types I and III collagen were each normal – suggesting a selective abnormality. As anticipated, collagen binding with all collagens was undetectable in the type 3 VWD subjects. Type 2A and 2B VWD subjects demonstrated reduced VWF:CB and VWF:CB/Ag ratios to all three types of collagen. Type 2M and 2N VWD subjects exhibited normal VWF:CB/Ag ratios to all three types of collagen, but one type 2M patient with an I1425F A1 loop mutation had a reduced VWF:CB/Ag ratio of 0.58. In the VWF A1 domain crystal structure, amino acid 1425 is in close proximity to amino acid 1399, suggesting the conformation of that region may be critical to type VI collagen binding to VWF. Since the frequency of the R1399H polymorphism is estimated to be 2% of the population (Sadler and Ginsburg, 1993), defective binding to type VI collagen may be an important contributor to the variability in the bleeding phenotype of VWD. Disclosures: Lentz: Novo Nordisk: Consultancy. Montgomery:GTI Diagnostics, Inc: Consultancy.

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