Cardiorenal damages in mice at early phase after intervention induced by angiotensin II, nephrectomy, and salt intake.

The interconnection of heart performance and kidney function plays an important role for maintaining homeostasis through a variety of physiological crosstalk between these organs. It has been suggested that acute or chronic dysfunction in one organ causes dysregulation in another one, like patients with cardiorenal syndrome. Despite its growing recognition as global health issues, still little is known on pathophysiological evaluation between the two organs.

Apelin expression is downregulated in T cells in a murine model of chronic colitis.

Apelin (APL), an endogenous ligand for APJ, has been reported to be upregulated in a murine model of acute colitis induced by sodium dextran sulfate, as well as inflammatory bowel diseases (IBD) in humans. However, the mechanisms and functions of APL/APJ axis in the pathogenesis of IBD are unclear. We herein analyzed CD4 T cells to determine the functions of APL in a murine model of chronic colitis induced in Rag deficient mice (Rag).

Disruption of entire locus leads to embryonic lethality by diminished gene expression and enhanced p53 pathway.

In vivo function of CDK5 and Abl enzyme substrate 2 (Cables2), belonging to the Cables protein family, is unknown. Here, we found that targeted disruption of the entire locus () caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of , 50% down-regulation of abutting on the locus, and up-regulation of p53-target genes in gastrulas.

Loss of PRMT1 in the central nervous system (CNS) induces reactive astrocytes and microglia during postnatal brain development.

PRMT1, a major arginine methyltransferase, plays critical roles in transcription, DNA damage response, and cell proliferation. Although we have previously discovered the crucial roles of PRMT1 for oligodendrocyte lineage progression in the central nervous system of neural stem cell-specific PRMT1 conditional knockout (PRMT1-CKO) mice, the context of other glial cell states that may cause the hypomyelination phenotype in PRMT1-CKO mice has not been explored so far. Here, we performed RNA-seq of the neonatal cortices of PRMT1-CKO mice to reveal overall gene expression changes and show the up-regulation of inflammatory signaling which is generally mediated by astrocytes and microglia in advance of the myelination defects.

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease that is caused by the dysregulation of alveolar epithelial type II cells (AEC II). The mechanisms involved in the progression of IPF remain incompletely understood, although the immune response accompanied by p38 mitogen-activated protein kinase (MAPK) activation may contribute to some of them. This study aimed to examine the association of p38 activity in the lungs with bleomycin (BLM)-induced pulmonary fibrosis and its transcriptomic profiling.

Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming.

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS).

Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart.

Background: The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood.

Methods: To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide-NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function.

Cooperative action of APJ and α1A-adrenergic receptor in vascular smooth muscle cells induces vasoconstriction.

The apelin receptor (APJ), a receptor for apelin and elabela/apela, induces vasodilation and vasoconstriction in blood vessels. However, the prolonged effects of increased APJ-mediated signalling, involving vasoconstriction, in smooth muscle cells have not been fully characterized. Here, we investigated the vasoactive effects of APJ gain of function under the control of the smooth muscle actin (SMA) gene promoter in mice.

Gestational changes in PRMT1 expression of murine placentas.

Introduction: In mammals, the placenta is an organ that is required to maintain the development of fetus during pregnancy. Although the proper formation of placenta is in part regulated by the post-translational modifications of proteins, little is known regarding protein arginine methylation during placental development. Here, we characterized developmental expression of protein arginine methyltransferase 1 (PRMT1) in mouse placentas.

Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives.

Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation.

ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage.

Aims: Elabela/Toddler/Apela (ELA) has been identified as a novel endogenous peptide ligand for APJ/Apelin receptor/Aplnr. ELA plays a crucial role in early cardiac development of zebrafish as well as in maintenance of self-renewal of human embryonic stem cells. Apelin was the first identified APJ ligand, and exerts positive inotropic heart effects and regulates the renin-angiotensin system.

Hydralazine is involved in tele-methylhistamine metabolism by inhibiting monoamine oxidase B in pregnancy-associated hypertensive mice.

Hypertensive disorders of pregnancy globally affect 6-8% of gestation and remain a major cause of both foetal and maternal morbidity and mortality. However, the antihypertensive medications for the patients of this disease are strictly limited due to the teratogenic potentials. Here, we found that tele-methylhistamine (tMH) increased in response to the administration of hydralazine (Hdz), a vasodilative agent, in the pregnancy-associated hypertensive (PAH) mice.

Angiodysplasia in embryo lacking protein arginine methyltransferase 1 in vascular endothelial cells.

Protein arginine methyltransferase 1 (PRMT1) is involved in multiple cellular functions including proliferation and differentiation. Although PRMT1 is expressed in vascular endothelial cells (ECs), which are responsible for angiogenesis during embryonic development, its role has remained elusive. In this study, we generated endothelial-specific prmt1-knockout (Prmt1-ECKO) mice, and found that they died before embryonic day 15.

Long-Range Control of Renin Gene Expression in Tsukuba Hypertensive Mice.

Renin, a rate-limiting enzyme in the renin-angiotensin system, is regulated to maintain blood pressure homeostasis: renin gene expression in the kidney is suppressed in a hypertensive environment. We found that expression of a 15-kb human RENIN (hREN) transgene was aberrantly upregulated (>4.2-fold), while the endogenous mouse renin (mRen) gene was suppressed (>1.

Unique pH dynamics in GABAergic synaptic vesicles illuminates the mechanism and kinetics of GABA loading.

GABA acts as the major inhibitory neurotransmitter in the mammalian brain, shaping neuronal and circuit activity. For sustained synaptic transmission, synaptic vesicles (SVs) are required to be recycled and refilled with neurotransmitters using an H(+) electrochemical gradient. However, neither the mechanism underlying vesicular GABA uptake nor the kinetics of GABA loading in living neurons have been fully elucidated.

Embryonic Intra-Aortic Clusters Undergo Myeloid Differentiation Mediated by Mesonephros-Derived CSF1 in Mouse.

The aorta-gonad-mesonephros (AGM) region contains intra-aortic clusters (IACs) thought to have acquired hematopoietic stem cell (HSC) potential in vertebrate embryos. To assess extrinsic regulation of IACs in the AGM region, we employed mouse embryos harboring a Sall1-GFP reporter gene, which allows identification of mesonephros cells based on GFP expression. Analysis of AGM region tissue sections confirmed mesonephros GFP expression.

Lactation Is a Risk Factor of Postpartum Heart Failure in Mice with Cardiomyocyte-specific Apelin Receptor (APJ) Overexpression.

The G protein-coupled receptor APJ and its ligand apelin are highly expressed in cardiovascular tissues and are associated with the regulation of blood pressure and cardiac function. Although accumulating evidence suggests that APJ plays a crucial role in the heart, it remains unclear whether up-regulation of APJ affects cardiac function. Here we generated cardiomyocyte-specific APJ-overexpressing (APJ-TG) mice and investigated the cardiac phenotype in APJ-TG mice.

Ground-based assessment of JAXA mouse habitat cage unit by mouse phenotypic studies.

The Japan Aerospace Exploration Agency developed the mouse Habitat Cage Unit (HCU) for installation in the Cell Biology Experiment Facility (CBEF) onboard the Japanese Experimental Module ("Kibo") on the International Space Station. The CBEF provides "space-based controls" by generating artificial gravity in the HCU through a centrifuge, enabling a comparison of the biological consequences of microgravity and artificial gravity of 1 g on mice housed in space. Therefore, prior to the space experiment, a ground-based study to validate the habitability of the HCU is necessary to conduct space experiments using the HCU in the CBEF.

PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination.

The development of vertebrate neurons requires a change in membrane phosphatidylcholine (PC) metabolism. Although PC hydrolysis is essential for enhanced axonal outgrowth mediated by phospholipase D (PLD), less is known about the determinants of PC metabolism on dendritic arborization. We show that protein arginine methyltransferase 8 (PRMT8) acts as a phospholipase that directly hydrolyzes PC, generating choline and phosphatidic acid.

Severe Hypomyelination and Developmental Defects Are Caused in Mice Lacking Protein Arginine Methyltransferase 1 (PRMT1) in the Central Nervous System.

Protein arginine methyltransferase 1 (PRMT1) is involved in cell proliferation, DNA damage response, and transcriptional regulation. Although PRMT1 is extensively expressed in the CNS at embryonic and perinatal stages, the physiological role of PRMT1 has been poorly understood. Here, to investigate the primary function of PRMT1 in the CNS, we generated CNS-specific PRMT1 knock-out mice by the Cre-loxP system.

Detection of ethanolamine altering in fetuses of pregnancy-associated hypertensive mice treated with vasodepressors by using UPLC and MALDI-TOF/MS.

Since serotonin, homocysteine and oxytocin are known to fluctuate during mammalian gestation, we screened amines altered in pregnant-associated hypertensive (PAH) mice by tagging their amino groups with 6-aminoquinoline carbamoyl (AQC) group in concert with ultra high-performance liquid chromatography (UPLC). Interestingly, a candidate amine significantly increased in PAH mice was recovered to the basal level, when treated with antihypertensive drugs. Mass spectrometric analyses indicated that the molecular mass of this amine was 61.

Angiotensin II accelerates mammary gland development independently of high blood pressure in pregnancy-associated hypertensive mice.

Angiotensin II (AngII) is a vasopressor hormone that has critical roles in maintenance of normal blood pressure and pathogenesis of cardiovascular diseases. We previously generated pregnancy-associated hypertensive (PAH) mice by mating female human angiotensinogen transgenic mice with male human renin transgenic mice. PAH mice exhibit hypertension in late pregnancy by overproducing AngII.

Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by Distinctive Pathways.

The renin-angiotensin system (RAS) plays a central role in blood pressure regulation. Although clinical and experimental studies have suggested that inhibition of RAS is associated with progression of anemia, little evidence is available to support this claim. Here we report that knockout mice that lack angiotensin II, including angiotensinogen and renin knockout mice, exhibit anemia.