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      Insights into Mechanisms Responsible for Mesangial Alterations Associated with Fibrogenic Glomerulopathic Light Chains

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          Our previous studies have shown that human mesangial cells (HMCs) incubated with fibrogenic glomerulopathic monoclonal light chains (G-LCs) obtained from the urine of patients with light chain deposition disease produce increased extracellular matrix (ECM) when compared with HMCs not exposed to fibrogenic LCs. This overproduction of ECM proteins is regulated by transforming growth factor-β (TGF-β); blocking TGF-β normalizes the production of ECM proteins. All ECM proteins, after synthesis, have to go through the secretory pathway in the endoplasmic reticulum (ER) and Golgi complex for final maturation and secretion. Blocking the secretory pathway may reduce the accumulation of ECM proteins. We tested the effect of tunicamycin, a specific inhibitor of N-linked glycosylation in the ER which inhibited glycosylation and brefeldin A, an inhibitor of vesicle transport between the endoplasmic reticulum and the Golgi complex, on ECM protein production, both resulting in subsequent upregulation of glucose-regulated protein 78. Overproduction of fibronectin and tenascin by HMCs was normalized by tunicamycin and brefeldin A. Similarly, when HMCs were exposed to exogenous TGF-β, the increase in fibronectin was reversed by tunicamycin and brefeldin A. Exogenous platelet-derived growth factor-β (PDGF-β) did not induce fibronectin overproduction but significantly stimulated proliferation of HMCs. In summary, this study further supports the notion that fibrogenic G-LCs promote the accumulation of ECM proteins, through the actions of TGF-β. Importantly, the data indicate that altering protein trafficking in the ER results in impairment of secretion of proteins into the ECM. Furthermore, the data also reveal that PDGF-β and TGF-β act independently and that PDGF-β activation by itself cannot increase ECM proteins directly, but only by increasing the number of HMCs.

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          Most cited references 10

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          Setting the standards: quality control in the secretory pathway.

          A variety of quality control mechanisms operate in the endoplasmic reticulum and in downstream compartments of the secretory pathway to ensure the fidelity and regulation of protein expression during cell life and differentiation. As a rule, only proteins that pass a stringent selection process are transported to their target organelles and compartments. If proper maturation fails, the aberrant products are degraded. Quality control improves folding efficiency by retaining proteins in the special folding environment of the endoplasmic reticulum, and it prevents harmful effects that could be caused by the deployment of incompletely folded or assembled proteins.
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            ATF6 as a Transcription Activator of the Endoplasmic Reticulum Stress Element: Thapsigargin Stress-Induced Changes and Synergistic Interactions with NF-Y and YY1

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              The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteasome pathway and involves heat shock protein 70.

              Apolipoprotein B (apoB) is the major protein component of atherogenic lipoproteins of hepatic origin. In HepG2 cells, the standard cell culture model of human hepatic lipoprotein metabolism, there is a limited availability of core lipids in the endoplasmic reticulum for association with nascent apoB. Under these conditions, apoB is partially translocated, interacts with cytosolic Hsp70, and undergoes rapid degradation. We show that increasing the expression of Hsp70 in HepG2 cells promotes apoB degradation. In addition, apoB is polyubiquitinated and its degradation both normally and after Hsp70 induction is blocked by inhibitors of the proteasome. The apoB that accumulates after proteasome inhibition is endoplasmic reticulum-associated and can be assembled into lipoproteins and secreted if new lipid synthesis is stimulated. Thus, apoB is the first example of a wild-type mammalian protein whose secretion is regulated by degradation in the cytosol via the ubiquitin-proteasome pathway. Furthermore, targeting of this secretory protein to the proteasome is regulated by the molecular chaperone Hsp70 and the availability of apoB's lipid-ligands.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                June 2003
                04 July 2003
                : 94
                : 2
                : p28-p38
                Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, La., USA
                71288 Nephron Physiol 2003;94:p28–p38
                © 2003 S. Karger AG, Basel

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                Figures: 11, References: 25, Pages: 1
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