Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.

TGF-β: the master regulator of fibrosis

Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. The enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, receptor tyrosine kinases and G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation. GSK-3 is unusual in that it is normally active in cells and is primarily regulated through inhibition of its activity. Another peculiarity compared with other protein kinases is its preference for primed substrates, that is, substrates previously phosphorylated by another kinase. Several recent advances have improved our understanding of GSK-3 regulation in multiple pathways. These include the solution of the crystal structure of GSK-3, which has provided insight into GSK-3's penchant for primed substrates and the regulation of GSK-3 by serine phosphorylation, and findings related to the involvement of GSK-3 in the Wnt/beta-catenin and Hedgehog pathways. Finally, since increased GSK-3 activity may be linked to pathology in diseases such as Alzheimer's disease and non-insulin-dependent diabetes mellitus, several new GSK-3 inhibitors, such as the aloisines, the paullones and the maleimides, have been developed. Although they are just starting to be characterized in cell culture experiments, these new inhibitors hold promise as therapeutic agents.

GSK-3: tricks of the trade for a multi-tasking kinase.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the Committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Seventh Edition of the JCA Special Issue continues to maintain this methodology and rigor to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Seventh Edition, like its predecessor, has consistently applied the category and grading system definitions in the fact sheets. The general layout and concept of a fact sheet that was used since the fourth edition has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. The Seventh Edition discusses 87 fact sheets (14 new fact sheets since the Sixth Edition) for therapeutic apheresis diseases and medical conditions, with 179 indications, which are separately graded and categorized within the listed fact sheets. Several diseases that are Category IV which have been described in detail in previous editions and do not have significant new evidence since the last publication are summarized in a separate table. The Seventh Edition of the JCA Special Issue serves as a key resource that guides the utilization of therapeutic apheresis in the treatment of human disease. J. Clin. Apheresis 31:149-162, 2016. © 2016 Wiley Periodicals, Inc.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Sixth Special Issue

KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor–β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β–neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.

/pdf/losartan-an-at1-antagonist-prevents-aortic-aneurysm-in-a-shv76753if.pdf

Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.

β-Catenin not only regulates cell-to-cell adhesion by interacting with cadherin but also functions as a component of the Wnt signaling pathway (34). The Wnt signaling pathway is conserved evolutionally and regulates cellular proliferation and differentiation by stabilizing β-catenin (2, 37). The β-catenin gene is often mutated in human cancer, and in such cases the protein level of β-catenin increases (17, 35). Therefore, clarifying the regulation of β-catenin stabilization is important for understanding the molecular mechanism of tumor formation.

According to the most widely accepted current model, casein kinase Iα (CKIα) and glycogen synthase kinase 3β (GSK-3β) target cytoplasmic β-catenin for degradation in the absence of Wnt (13, 26, 42). Axin has been shown to form a complex with GSK-3β, CKIα, β-catenin, and adenomatous polyposis coli gene product (APC) (13, 16, 21, 26). In the Axin complex CKIα serves as a priming kinase that phosphorylates Ser45 of β-catenin and enhances the phosphorylation at Ser33, Ser37, and Thr41 of β-catenin by GSK-3β (26, 43). Phosphorylated β-catenin is ubiquitinated and degraded by the proteasome pathway (22).

When Wnt acts on its cell surface receptor consisting of Frizzled and lipoprotein receptor-related protein (LRP) 5/6 (9), Dvl induces the accumulation of β-catenin in the cytoplasm by inhibiting the GSK-3β-dependent phosphorylation of β-catenin (10, 20, 41). Accumulated β-catenin is translocated into the nucleus, where it binds to the transcription factors T-cell factor (Tcf) and lymphoid enhancer factor (Lef) and thereby stimulates the expression of various genes, including c-myc, cyclin D1, and Axin2 (2, 28, 37). Thus, Wnt stabilizes β-catenin and activates Tcf and Lef. Although CKIα- and GSK-3β-dependent phosphorylation is essential for the degradation of β-catenin in the Wnt pathway, a phosphorylation-independent pathway through Siah-1 has been found (27, 30). It has also been shown that release of Ca2+ from internal stores by the Gq pathway results in calpain-mediated degradation of β-catenin (25). Therefore, it is likely that there are multiple pathways to regulate the stability of β-catenin.

The Alzheimer's disease-linked gene presenilin1 forms a complex with GSK-3β, β-catenin, and the catalytic subunit of cyclic AMP (cAMP)-dependent protein kinase (PKA) (15). In the presenilin1 complex, PKA phosphorylates Ser45 of β-catenin and enhances the GSK-3β-dependent phosphorylation of β-catenin, suggesting that PKA and presenilin1 induce the downregulation of β-catenin independently of the Wnt-controlled Axin complex. Indeed, nuclear accumulation of β-catenin is observed in the epidermis of presenilin1-deficient mice (15). However, in contrast to the finding that PKA might function as a negative regulator of β-catenin stability, it has been shown that stimulation with prostaglandin E2 (PGE2), which activates PKA, increases the transcriptional activity of Tcf in HEK-293 cells, probably through phosphorylation and inhibition of GSK-3β (8). Thus, the molecular mechanism of the cross talk between the Wnt and PKA signaling pathways is largely unknown. In this study, we examined the effects of PKA on the ubiquitin-dependent degradation of β-catenin. We here show that phosphorylation of β-catenin at Ser675 by PKA stabilizes β-catenin by inhibiting its ubiquitination.

Phosphorylation of β-Catenin by Cyclic AMP-Dependent Protein Kinase Stabilizes β-Catenin through Inhibition of Its Ubiquitination

ANG II induces secretion and activation of transforming growth factor-β (TGF-β) by glomerular mesangial cells. However, the mechanisms that operate this are unclear. Thrombospondin-1 (TSP-1), which...

Angiotensin II induces thrombospondin-1 production in human mesangial cells via p38 MAPK and JNK: a mechanism for activation of latent TGF-β1

A-Kinase Anchoring Protein AKAP220 Binds to Glycogen Synthase Kinase-3β (GSK-3β) and Mediates Protein Kinase A-dependent Inhibition of GSK-3β

A 53-year-old-male patient was admitted to the Hiroshima University Hospital in August 2001, with a history of progressive cerebellar ataxia, notable by standing and gait disturbances. Brain computed tomography (CT) and magnetic resonance imaging (MRI) showed no signs of ischemic damage. Two weeks later, left axillary lymphadenopathy developed. The pathological finding was Hodgkin's disease (HD; a classical malignant lymphoma in an early stage). Serum antibodies against Purkinje's cells (anti-Tr antibody) were detected by immunohistochemical study. Thus, we diagnosed this as paraneoplastic cerebellar degeneration (PCD) associated HD. We immediately carried out chemotherapy (ABVD therapy), radiotherapy with 20-30 Gy, steroid pulse and intravenous immunoglobulin (IVIg) without neurologic improvement. The patient was subsequently treated by double filtration plasmapheresis (DFPP), leading to a marked improvement of standing and gait disturbances and to a reduction of autoantibodies, which became undetectable. We conclude that DFPP might be useful in treating patients with cerebellar ataxia, and should be considered as a therapeutic choice for it.

A case report of plasmapheresis in paraneoplastic cerebellar ataxia associated with anti-Tr antibody.

A 21-year-old man was admitted to Kure National Hospital with nephrotic syndrome in September 1996. He had suffered from an intractable pruritic skin rash and recurrent subcutaneous abscesses caused by the hyperimmunoglobulin E syndrome since the age of 18 months. Renal biopsy gave a diagnosis of membranoproliferative glomerulonephritis. Steroid therapy decreased urinary protein loss and hypoproteinemia, and his pruritic skin rash was improved. Patients with hyperimmunoglobulin E syndrome have a defective immune response, especially to Staphylococcus aureus infection. Continuous antigen stimulation may have caused this patient's renal histological damage as in immune complex glomerulonephritis.

Hyperimmunoglobulin E Syndrome Associated with Nephrotic Syndrome

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