Glomerular permeability for macromolecules depends partially on proper attachment of the glomerular epithelial cells (GEC) to the glomerular basement membrane (GBM). The latter requires integrity of the actin cytoskeleton, which in turn is regulated by specific actin-associated proteins. Since several glomerulopathies characterized by heavy proteinuria are associated with increased glomerular tumor necrosis factor a (TNF-a) expression, we studied the interaction of TNF-a with the actin cytoskeleton of cultured rat GEC. Incubation of GEC with 10 ng/ml TNF-a for variable time periods ranging from 15 min to 24 hr demonstrated a marked accentuation and redistribution of actin microfilaments, as shown by direct fluorescence analysis and confocal laser scanning microscopy. Quantitative biochemical determination of the G/total-actin ratio confirmed the above observations. Indeed, this ratio was significantly reduced, indicating substantial polymerization of G-actin and formation of F-actin. Concurrently, TNF-a rapidly induced tyrosine phosphorylation of both paxfillin and focal adhesion ki-nase, without affecting the expression levels of these two proteins. In addition, tyrosine phosphorylation of vinculin became evident, indicating involvement of this focal adhesion marker in the observed actin reorganization. Inhibition of tyrosine phosphorylation by genistein prevented the reorganization of the actin cytoskeleton by TNF-a. We condude that TNF-a induces substantial reorganization of actin cytoskeleton and focal adhesions. These effects occur simultaneously, with a prompt TNFa-induced tyrosine phosphorylation of paxillin and focal adhesion kinase, indicating that these proteins, known to regulate actin polymerization and formation of focal adhesions, may be directly involved in the mechanism controlling the observed actin redistribution. These findings suggest that the observed TNF-a-actin cytoskeleton interactions may relate to the pathogenesis of glomerulopathies with heavy proteinuria, in which increased glomerular expression of TNF-a is associated with disturbances in the attachment of podocytes to the GBM.
These results suggest that: (i) the PI3K/Akt/mTOR pathway is upregulated in murine lupus nephritis, thus justifying treatment with rapamycin; (ii) rapamycin not only blocks mTOR but also negatively regulates the PI3K/Akt/mTOR pathway; and (iii) rapamycin is an effective treatment of murine lupus nephritis. Examination of the PI3K/Akt/mTOR pathway may offer new insights into the pathogenesis of lupus nephritis in humans and may lead to more individualized and less toxic treatment.
Considerable controversy currently exists in the literature concerning the mode of catheter placement and its impact on the technical success of peritoneal dialysis (PD). We decided to compare the impact of the surgical versus the percutaneous insertion technique on peritoneal dialysis catheter (PDCs) complications and survival. Our study population comprised 152 patients in whom 170 PDCs were inserted between January 1990 and December 2007 at the main PD unit on the island of Crete. Eighty four catheters were surgically placed (S group) and 86 were placed percutaneously by nephrologists (N group). The total experience accumulated was 4997 patient-months. The overall complications did not differ between the two groups. Only early leakage was more frequent in N group than S group (10.3 versus 1.9 episodes per 1000 patient-months; p < 0.001). However, it was easily treated and did not constitute a cause of early catheter removal. Catheter survival was 91.1%, 80.7%, and 73.2%, in the S group versus 89.5%, 83.7%, and 83.7% for the N group at 1, 2, and 3 years, respectively (p = 0.2). Catheter survival has significantly increased over the last decade. Factors positively affecting PDC survival appeared to be the use of mupirocin for exit site care and the utilization of the coiled type of catheter, practices implemented mainly after 1999. Peritonitis-free survival and patient survival were not associated with the mode of placement, while in Cox regression analysis, were longer in patients treated with automated PD. The placement mode did not affect PD outcomes. Percutaneous implantation proved a safe, simple, low cost, immediately available method for PDC placement and helped to expand our PD program.
The actin microfilaments are well known dynamic structures that support and organize the cell membrane and functions associated with the membrane such as ion channels and transporters. In addition, many aspects of cellular physiology seem to be actively modulated by changes in actin cytoskeleton dynamics, which involve reorganization and restructuring of the filaments. For both of these reasons, the actin cytoskeleton has attracted special attention since the early days of cell volume regulation research. Mechanisms controlling the actin equilibrium in response to external stimuli were studied and the signaling cascades leading to the regulation of actin cytoskeleton dynamics have been partially elucidated. They include: a) activation of specific actin binding proteins that regulate actin polymerization dynamics, b) activation of protein kinases or phosphatases regulating phosphorylation of specific cytoskeletal proteins and c) activation of signal transduction pathways leading from membrane receptor activation to actin reorganization involving small GTPases of the Rho and Rac families. These intracellular signal transducers are activated by extracellular stimuli that include hormones, growth factors, cytokines, or ions, many of them in turn are partially known to participate in cell volume regulation. These findings provide strong evidence that the actin cytoskeleton is involved in cell volume regulation by sensing and mediating extracellular signals.
PEIT is a safe and effective nonsurgical treatment for patients with p-HPT, who are unsuitable for surgical intervention.
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