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Mechanosensation is a fundamental function through which cells sense mechanical stimuli by initiating intracellular ion currents. Ion channels play a pivotal role in this process by orchestrating a cascade of events leading to the activation of downstream signaling pathways in response to particular stimuli. Piezo1 is a cation channel that reacts with Ca2+ influx in response to pressure sensation evoked by tension on the cell lipid membrane, originating from cell–cell, cell–matrix, or hydrostatic pressure forces, such as laminar flow and shear stress. The application of such forces takes place in normal physiological processes of the cell, but also in the context of different diseases, where microenvironment stiffness or excessive/irregular hydrostatic pressure dysregulates the normal expression and/or activation of Piezo1. Since Piezo1 is expressed in several blood cell lineages and mutations of the channel have been associated with blood cell disorders, studies have focused on its role in the development and function of blood cells. Here, we review the function of Piezo1 in different blood cell lineages and related diseases, with a focus on megakaryocytes and platelets. [ABSTRACT FROM AUTHOR]

A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI)--a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in [Ent1-/-] mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications., Introduction Acute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to [...]

Past studies described interactions between normal megakaryocytes, the platelet precursors, and bone cell precursors in the bone marrow. This relationship has also been studied in context of various mutations associated with increased number of megakaryocytes. The current study is the first to examine the effects of megakaryocytes from transgenic mice carrying the most common mutation that causes primary myelofibrosis (PMF) in humans (JAK2V617F) on bone cell differentiation. Organ level assessments of mice using micro-computed tomography showed decreased bone volume in JAK2V617F males, compared to matching controls. Tissue level histology revealed increased deposition of osteoid (bone matrix prior mineralization) in these mutated mice, suggesting an effect on osteoblast differentiation. Mechanistic studies using a megakaryocyte-osteoblast co-culture system, showed that both wild type or JAK2V617F megakaryocytes derived from male mice inhibited osteoblast differentiation, but JAK2V617F cells exerted a more significant inhibitory effect. A mouse mRNA osteogenesis array showed increased expression of Noggin, Chordin, Alpha-2-HSglycoprotein, Collagen type IV alpha 1 and Collagen type XIV alpha 1 (mostly known to inhibit bone differentiation), and decreased expression of alkaline phosphatase, Vascular cell adhesion molecule 1, Sclerostin, Distal-less homeobox 5 and Collagen type III alpha 1 (associated with osteogenesis) in JAK2V617F megakaryocytes, compared to controls. This suggested that the mutation re-programs megakaryocytes to express a cluster of genes, which together could orchestrate greater suppression of osteogenesis in male mice. These findings provide mechanistic insight into the effect of JAK2V617F mutation on bone, encouraging future examination of patients with this or other PMF-inducing mutations. [ABSTRACT FROM AUTHOR]

Background Acute renal failure from ischernia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischernia are urgently needed. Here, we identified a novel pathway of renal protection from ischernia using ischernic preconditioning (IP). Methods and Findings For this purpose, we utilized a recently developed model of renal ischernia and IP via a hanging weight system that allows repeated and atraurnatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in genetargeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in [A1.sup.-/-], [A2A.sup.-/-], or [A3AR.sup.-/-] mice. In contrast, protection from ischernia was abolished in [A2BAR.sup.-/-] mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1 115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60-6583 dramatically improved renal function and histology following ischernia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bonemarrow chimera conferred kidney protection selectively to renal A2BARs. Conclusions These results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischermia., Introduction Acute renal failure is defined as a rapid decrease in the glomerular filtration rate (GFR), occurring over a period of minutes to days [1]. The causes of acute renal [...]

Adenosine has been described as playing a role in the control of inflammation, but it has not been certain which of its receptors mediate this effect. Here, we generated an [...]

Abstract Background Ependymal cells form a protective monolayer between the brain parenchyma and cerebrospinal fluid (CSF). They possess motile cilia important for directing the flow of CSF through the ventricular system. While ciliary beat frequency in airway epithelia has been extensively studied, fewer reports have looked at the mechanisms involved in regulating ciliary beat frequency in ependyma. Prior studies have demonstrated that ependymal cells express at least one purinergic receptor (P2X7). An understanding of the full range of purinergic receptors expressed by ependymal cells, however, is not yet complete. The objective of this study was to identify purinergic receptors which may be involved in regulating ciliary beat frequency in lateral ventricle ependymal cells. Methods High-speed video analysis of ciliary movement in the presence and absence of purinergic agents was performed using differential interference contrast microscopy in slices of mouse brain (total number of animals = 67). Receptor identification by this pharmacological approach was corroborated by immunocytochemistry, calcium imaging experiments, and the use of two separate lines of knockout mice. Results Ciliary beat frequency was enhanced by application of a commonly used P2X7 agonist. Subsequent experiments, however, demonstrated that this enhancement was observed in both P2X7+/+ and P2X7-/- mice and was reduced by pre-incubation with an ecto-5'-nucleotidase inhibitor. This suggested that enhancement was primarily due to a metabolic breakdown product acting on another purinergic receptor subtype. Further studies revealed that ciliary beat frequency enhancement was also induced by adenosine receptor agonists, and pharmacological studies revealed that ciliary beat frequency enhancement was primarily due to A2B receptor activation. A2B expression by ependymal cells was subsequently confirmed using A2B-/-/β-galactosidase reporter gene knock-in mice. Conclusion This study demonstrates that A2B receptor activation enhances ciliary beat frequency in lateral ventricle ependymal cells. Ependymal cell ciliary beat frequency regulation may play an important role in cerebral fluid balance and cerebrospinal fluid dynamics.

An investigative committee at the University of Colorado Denver recently reported multiple findings of data falsification and fabrication or lack of underlying supporting data regarding Figures 1, 2, 3, 5, [...]