Although angiotensin II (Ang II) type 1 receptor antagonist ameliorates proteinuria, its pharmacological mechanism and the differential roles of Ang II type 1 receptor (AT1R) and type 2 receptor (AT2R) are not well understood. We analyzed the effect of Ang II type 1 receptor antagonist on proteinuria caused by antibody against nephrin, a functional molecule of glomerular slit diaphragm and dysfunction of which is involved in the development of proteinuria in several glomerular diseases. We show here that AT1R antagonist ameliorated proteinuria by preventing a reduction in the functional molecules of the slit diaphragm. We also analyzed the role of AT1R- or AT2R-mediated actions on the expression of the slit diaphragm molecules in an in vivo study of normal rat and in an in vitro study of cultured podocytes. AT1R-mediated action hampered the mRNA expression of the slit diaphragm molecules, whereas AT2R-mediated action enhanced it. These findings indicate that Ang II receptor subtypes play opposite roles in regulating the barrier function of glomerular capillary wall and that the enhancement of AT2R stimulation may serve as a potential therapeutic strategy for proteinuria.
When a Cd-resistant strain (301 N) and a Cd-sensitive strain (101 N ) of Saccharomyces cereuisiae were incubated in medium containing Cd2+, a large proportion of the cellular Cd2+ was found in the cytosol of strain 301 N, but not in that of strain 101N. Approximately 65% of the cellular Cd2+ was released from strain 301 N after treatment with chitosan, which affects cell membrane permeability. About 807; of the cellular Cd2+ released from strain 301 N by chitosan treatment was detected in a 30000-10000 molecular weight fraction prepared by ultrafiltration. The distribution of Cd2+ into the cytosol in strain 301N was inhibited in the presence of cycloheximide. The proportion of cellular Cu2+ or Zn2+ present in the cytosol after incubation with these ions was similar for the two strains (about 40"/,).
Background/Aims: Multi-glycoside from Tripterygium wilfordii Hook f. (GTW) is used for various immune and inflammatory diseases including renal diseases represented by mesangial proliferative glomerulonephritis (MsPGN) in China. However, there have been no fundamental studies on the operating mechanism of GTW on MsPGN. The aim of this study is to examine as the first step the effects of GTW on acute injurious process such as mesangial injury and proteinuria in an acute and reversible Thy.1.1 glomerulonephritis (Thy1.1GN) model and then to clarify the action mechanism of GTW at molecular level by examining its effects on various injurious factors in this model. Methods: Thy1.1 GN was induced in rats by a single intravenous injection with 500 µg of anti-Thy1.1 mAb 1-22-3. Daily oral administration of GTW and vehicle as a control was started from 3 days before injection of mAb to the day of sacrifice in each experiment. Fourteen rats were randomly divided into 2 groups, GTW-treated and vehicle-treated groups, and sacrificed on day 14 in experiment 1 or on day 7 in experiment 2 after induction of Thy1.1 GN. Proteinuria was determined on days 1, 3, 5, 7, 10 and 14 in experiment 1 or on 1, 3, 5 and 7 in experiment 2. From blood and kidneys taken at sacrifice, blood biochemical parameters, mesangial morphological changes, glomerular macrophage infiltration, and glomerular mRNA expression of cytokines were examined. Results: In experiment 1, proteinuria and mesangial matrix expansion were significantly attenuated by GTW treatment. In experiment 2, GTW treatment significantly ameliorated proteinuria, mesangial lesions and macrophage accumulation in glomerulus. In addition, it significantly reduced the glomerular expression of mRNA for PDGF, MCP-1 and IL-2. Conclusion: GTW ameliorated not only proteinuria but also mesangial alterations in Thy1.1 GN most likely by reducing expression of injurious cytokines, indicating that GTW has suppressive effects on acute inflammatory changes in glomeruli.
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