scholarly journals Fcα Receptor (Cd89) Mediates the Development of Immunoglobulin a (Iga) Nephropathy (Berger's Disease)

1999 ◽  
Vol 191 (11) ◽  
pp. 1999-2010 ◽  
Author(s):  
Pierre Launay ◽  
Béatrice Grossetête ◽  
Michelle Arcos-Fajardo ◽  
Emmanuelle Gaudin ◽  
Sonia P. Torres ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Molecular Mechanism ◽  
Severe Combined Immunodeficiency ◽  
Immunoglobulin A ◽  
In Vivo Model ◽  
Matrix Expansion ◽  
Recombination Activating Gene ◽  
New Treatments

The pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN), the most prevalent form of glomerulonephritis worldwide, involves circulating macromolecular IgA1 complexes. However, the molecular mechanism(s) of the disease remain poorly understood. We report here the presence of circulating soluble FcαR (CD89)-IgA complexes in patients with IgAN. Soluble CD89 was identified as a glycoprotein with a 24-kD backbone that corresponds to the expected size of CD89 extracellular domains. To demonstrate their pathogenic role, we generated transgenic (Tg) mice expressing human CD89 on macrophage/monocytes, as no CD89 homologue is found in mice. These mice spontaneously developed massive mesangial IgA deposition, glomerular and interstitial macrophage infiltration, mesangial matrix expansion, hematuria, and mild proteinuria. The molecular mechanism was shown to involve soluble CD89 released after interaction with IgA. This release was independent of CD89 association with the FcRγ chain. The disease was induced in recombination activating gene (RAG)2−/− mice by injection of serum from Tg mice, and in severe combined immunodeficiency (SCID)-Tg mice by injection of patients' IgA. Depletion of soluble CD89 from serum abolished this effect. These results reveal the key role of soluble CD89 in the pathogenesis of IgAN and provide an in vivo model that will be useful for developing new treatments.

scholarly journals A Yes-Associated Protein (YAP) and Insulin-Like Growth Factor 1 Receptor (IGF-1R) Signaling Loop Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3812
Author(s):  
Mai-Huong T. Ngo ◽  
Sue-Wei Peng ◽  
Yung-Che Kuo ◽  
Chun-Yen Lin ◽  
Ming-Heng Wu ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Combination Index ◽  
Specific Inhibitor ◽  
In Vivo Model ◽  
Mrna Levels ◽  
Margin Distribution ◽  
Related Proteins ◽  
Emt Markers

The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. Method: Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM–LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. Results: Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). Conclusion: A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.

The Role of Mannose Receptor in IgE Production in an in vivo Model of Cat Allergy

2011 ◽  
Vol 127 (2) ◽  
pp. AB152-AB152
Author(s):  
A.M. Ghaemmaghami ◽  
M. Emara ◽  
L. Martinez-Pomares ◽  
F. Shakib
Keyword(s):  
Mannose Receptor ◽  
In Vivo Model ◽  
Cat Allergy

scholarly journals The Role of IgA in the Pathogenesis of IgA Nephropathy

2019 ◽  
Vol 20 (24) ◽  
pp. 6199 ◽  
Author(s):  
Martina Perše ◽  
Željka Večerić-Haler
Keyword(s):  
Iga Nephropathy ◽  
Genetic Factors ◽  
Immunoglobulin A ◽  
Symbiotic Relationship ◽  
Biological Functions ◽  
Antibody Isotype ◽  
Microbial Invasion ◽  
Iga Antibodies ◽  
Interaction With Receptors

Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans, predominantly present in the mucosal areas where its main functions are the neutralization of toxins, prevention of microbial invasion across the mucosal epithelial barrier, and simultaneous maintenance of a physiologically indispensable symbiotic relationship with commensal bacteria. The process of IgA biosynthesis, interaction with receptors, and clearance can be disrupted in certain pathologies, like IgA nephropathy, which is the most common form of glomerulonephritis worldwide. This review summarizes the latest findings in the complex characteristics of the molecular structure and biological functions of IgA antibodies, offering an in-depth overview of recent advances in the understanding of biochemical, immunologic, and genetic factors important in the pathogenesis of IgA nephropathy.

Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of α-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility

2005 ◽  
Vol 288 (3) ◽  
pp. H1477-H1490 ◽  
Author(s):  
Francesca J. Davis ◽  
Jyothish B Pillai ◽  
Madhu Gupta ◽  
Mahesh P. Gupta
Keyword(s):  
Cardiac Myocytes ◽  
Histone Deacetylases ◽  
Contractile Function ◽  
Trichostatin A ◽  
In Vivo Model ◽  
Ang Ii ◽  
Cardiac Contractile Function ◽  
Noticeable Effect

Histone deacetylases (HDACs) are a family of enzymes that catalyze the removal of acetyl groups from core histones, resulting in change of chromatin structure and gene transcription activity. In the heart, HDACs are targets of hypertrophic signaling, and their nonspecific inhibition by trichostatin A (TSA) attenuates hypertrophy of cultured cardiac myocytes. In this study, we examined the effect of TSA on two major determinants of cardiac contractility: α-myosin heavy chain (MHC) expression and microtubular composition and organization. TSA upregulated the expression of α-MHC in cultured cardiac myocytes, as well as in an in vivo model of hypothyroid rats. Studies designed to delineate mechanisms of α-MHC induction by TSA revealed an obligatory role of early growth response factor-1 on activation of the α-MHC promoter. Concurrently, TSA downregulated the expression of α- and β-tubulins and prevented the induction of tubulins by a hypertrophy agonist, ANG II. The ANG II-mediated increased proportion of α- and β-tubulins associated with polymerized microtubules was also markedly reduced after treatment of cells by TSA. Results obtained from immunofluorescent microscopy indicated that TSA had no noticeable effect on the organization of cardiac microtubules in control cells, whereas it prevented the ANG II-induced dense parallel linear arrays of microtubules to a profile similar to that of controls. Together, these results demonstrate that inhibition of HDACs by TSA regulates the cardiac α-MHC and tubulins in a manner predictive of improved cardiac contractile function. These studies improve our understanding of the role of HDACs on cardiac hypertrophy with implications in development of new therapeutic agents for treatment of cardiac abnormalities.

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