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1.
Acta Physiol (Oxf) ; 208(1): 25-40, 2013 May.
Article in English | MEDLINE | ID: mdl-23432924

ABSTRACT

Acute kidney injury (AKI) induced by ischaemia and reperfusion (I/R) injury is a common and severe clinical problem. Vascular dysfunction, immune system activation and tubular epithelial cell injury contribute to functional and structural deterioration. The search for novel therapeutic interventions for I/R-induced AKI is a dynamic area of experimental research. Pharmacological targeting of injury mediators and corresponding intracellular signalling in endothelial cells, inflammatory cells and the injured tubular epithelium could provide new opportunities yet may also pose great translational challenge. Here, we focus on signalling mediators, their receptors and intracellular signalling pathways which bear potential to abrogate cellular processes involved in the pathogenesis of I/R-induced AKI. Sphingosine 1 phosphate (S1P) and its respective receptors, cytochrome P450 (CYP450)-dependent vasoactive eicosanoids, NF-κB- and protein kinase-C (PKC)-related pathways are representatives of such 'druggable' pleiotropic targets. For example, pharmacological agents targeting S1P and PKC isoforms are already in clinical use for treatment for autoimmune diseases and were previously subject of clinical trials in kidney transplantation where I/R-induced AKI occurs as a common complication. We summarize recent in vitro and in vivo experimental studies using pharmacological and genomic targeting and highlight some of the challenges to clinical application of these advances.


Subject(s)
Acute Kidney Injury/metabolism , Kidney/blood supply , Kidney/metabolism , Reperfusion Injury/metabolism , Signal Transduction , Acute Kidney Injury/genetics , Acute Kidney Injury/physiopathology , Acute Kidney Injury/therapy , Animals , Cytochrome P-450 Enzyme System/metabolism , Eicosanoids/metabolism , Humans , Kidney/drug effects , Lysophospholipids/metabolism , Molecular Targeted Therapy , NF-kappa B/metabolism , Prognosis , Protein Kinase C/metabolism , Receptors, Lysosphingolipid/metabolism , Renal Circulation , Reperfusion Injury/genetics , Reperfusion Injury/physiopathology , Reperfusion Injury/therapy , Signal Transduction/drug effects , Sphingosine/analogs & derivatives , Sphingosine/metabolism
3.
Z Kardiol ; 90(5): 307-18, 2001 May.
Article in German | MEDLINE | ID: mdl-11452892

ABSTRACT

Arteriosclerosis and the development of restenosis still remain a significant clinical problem. Migration of vascular smooth muscle cells from the media to the intima and cell proliferation are the hallmarks of the underlying pathomechanisms. Cell migration requires chemotaxis, phenotypic changes of cells, cell adhesive and de-adhesive events and the coordinated remodeling of the extracellular matrix. One of the phenotypic changes induced in migrating cells is the increased expression of urokinase plasminogen activator (uPA) and of its specific receptor uPAR. They are polarized to the leading edge of migrating cells. Both uPA and uPAR are key mediators of extracellular proteolysis. They participate in extracellular matrix remodeling, activate cells and enable them to migrate and invade into different tissue layers. UPA/uPAR are multifunctional proteins influencing a great variety of signal transduction pathways ultimately culminating in the regulation of cell migration and proliferation. In addition to time- and space-confined proteolysis this powerful system can mediate chemotaxis, cell adhesion and gene expression, partly by interacting in concert with integrins, G proteins, or with yet unidentified coreceptors or adapter molecules. Interaction with the uPA/uPAR system or components of its specific signal transduction pathways may serve as a guide for the development of effective therapeutic strategies to prevent arteriosclerosis and restenosis after percutaneous arterial angioplastic interventions.


Subject(s)
Arteriosclerosis/physiopathology , Coronary Artery Disease/physiopathology , Receptors, Cell Surface/physiology , Tissue Plasminogen Activator/physiology , Animals , Arteriosclerosis/therapy , Cell Division/physiology , Cell Movement/physiology , Coronary Artery Disease/therapy , Humans , Muscle, Smooth, Vascular/physiopathology
4.
J Biol Chem ; 275(50): 39466-73, 2000 Dec 15.
Article in English | MEDLINE | ID: mdl-10995743

ABSTRACT

Janus kinases Jak1 and Tyk2 play an important role in urokinase-type plasminogen activator (uPA)-dependent signaling. We have recently demonstrated that both kinases are associated with the uPA receptor (uPAR) and mediate uPA-induced activation of signal transducers and activators of transcription (Stat1, Stat2, and Stat4) in human vascular smooth muscle cells (VSMC). Janus kinases are not only required for Stat activation but may also interfere with other intracellular signaling pathways. Here we report that in VSMC, Tyk2 interacts with a downstream signaling cascade involving phosphatidylinositol 3-kinase (PI3-K). We demonstrate that uPA induces PI3-K activation, which is abolished in VSMC expressing the dominant negative form of Tyk2. The regulatory subunit p85 of PI3-K co-immunoprecipitates with Tyk2 but not with Jak1, Jak2, or Jak3, and uPA stimulation increases the PI3-K activity in Tyk2 immunoprecipitates. Tyk2 directly binds to either of the two Src homology 2(SH2)p85 domains in a uPA-dependent fashion. We provide evidence that the Tyk2-mediated PI3-K activation in response to uPA is required for VSMC migration. Thus, two unrelated structurally distinct specific inhibitors of PI3-K, wortmannin and LY294002, prevent VSMC migration induced by uPA. No migratory effect of uPA was observed in VSMC expressing the dominant negative form of Tyk2. Our results underscore the versatile function of Tyk2 in uPA-related intracellular signaling and indicate that PI3-K plays a selective role in the regulation of VSMC migration.


Subject(s)
Muscle, Smooth, Vascular/cytology , Phosphatidylinositol 3-Kinases/metabolism , Protein-Tyrosine Kinases , Proteins/metabolism , Urokinase-Type Plasminogen Activator/metabolism , Androstadienes/pharmacology , Blotting, Northern , Cell Movement , Cells, Cultured , Chemotaxis , Chromones/pharmacology , Cytoskeleton , Enzyme Activation , Enzyme Inhibitors/pharmacology , Genes, Dominant , Glutathione Transferase/metabolism , Humans , Microscopy, Fluorescence , Microscopy, Video , Morpholines/pharmacology , Precipitin Tests , Protein Binding , Proteins/genetics , RNA/metabolism , Recombinant Fusion Proteins/metabolism , Signal Transduction , TYK2 Kinase , Time Factors , Transcription, Genetic , Tyrosine/metabolism , Wortmannin , src Homology Domains
5.
Article in English | MEDLINE | ID: mdl-8508038

ABSTRACT

This study investigated the developmental, demographic, educational, and psychosocial outcome of 36 adults with third-generation familial dyslexia. Control subjects were 44 unaffected age-matched family members. Compared with control subjects, those with familial dyslexia 1) had similar incidences of perinatal complications, left-handedness, and right-left confusion but reported more early speech/language problems; 2) performed worse in reading and spelling but had similar educational achievement; 3) were more likely to report depression/anxiety symptoms and to have attention-deficit disorder with hyperactivity; and 4) were similar in medical history, marital stability, and mean income. Data suggest that, despite continued isolated reading deficits, carefully selected subjects with adult familial dyslexia do not show the previously described downward course of the learning-disabled population.


Subject(s)
Dyslexia/psychology , Adult , Behavior , Dyslexia/genetics , Education , Female , Humans , Male , Middle Aged , Prognosis , Psychiatric Status Rating Scales , Retrospective Studies , Wechsler Scales
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