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      AT 1-Receptor Antagonists Abolish Glomerular MCP-1 Expression in a Model of Mesangial Proliferative Glomerulonephritis

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          Background: Glomerular accumulation of macrophages/monocytes (M/M) is a typical early feature in the course of anti-thymocyte serum (ATS)-induced nephritis. We have previously shown that glomerular synthesis and expression of monocyte-chemoattractant protein-1 (MCP-1) occurs before influx of M/M and a neutralizing anti-MCP-1 antibody reduced this cell infiltrate by one third. The present study was undertaken to test the effect of two angiotensin II type 1 (AT<sub>1</sub>) receptor antagonists, losartan and irbesartan, on ATS-stimulated MCP-1 expression as well as glomerular influx of M/M. Methods: Treatment of rats with either losartan or irbesartan was started 24 h before administration of ATS. After 24 h, MCP-1 mRNA expression was evaluated by RT-PCR and Northern blots. MCP-1 protein was determined by Western blots and chemotactic factors released from isolated glomeruli were measured by chemotactic assay. Kidney sections were stained for rabbit IgG, complement C3, and M/M (ED1 antigen). Results: Both AT<sub>1</sub>-receptor antagonists caused a significant, but not total reduction in MCP-1 mRNA and protein expression 24 h after injection of ATS. Treatment with losartan or irbesartan also reduced the chemotactic activity of isolated glomeruli from nephritic animals. Quantification of ED1-positive cells revealed that losartan as well as irbesartan reduced glomerular M/M invagination in nephritic rats by approximately 30–50%. However, treatment with AT<sub>1</sub>-receptor antagonists did not influence binding of ATS to mesangial cells and subsequent complement activation indicating that the attenuated MCP-1 expression is not due to differences in delivery and binding of ATS to mesangial cells. Conclusion: Our data indicate that short-term antagonism of AT<sub>1</sub> receptors abolished the early glomerular MCP-1 expression and M/M influx. These results indicate that angiotensin II may exert immunomodulatory effects in vivo and adds a new mechanism showing how this vasopeptide may be involved in the pathogenesis of renal diseases.

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          p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells.

          Superoxide anion formation is vital to the microbicidal activity of phagocytes. Recently, however, there is accumulating evidence that it is also involved in cell growth in vascular smooth muscle cells (VSMCs). We have shown that the hypertrophic agent angiotensin II stimulates superoxide production by activating the membrane-bound NADH/NADPH oxidase and that inhibition of this oxidase attenuates vascular hypertrophy. However, the molecular identity of this oxidase in VSMCs is unknown. We have recently cloned the cytochrome b558 alpha-subunit, p22(phox) (one of the key electron transfer elements of the NADPH oxidase in phagocytes), from a rat VSMC cDNA library, but its role in VSMC oxidase activity remains unclarified. Here we report that the complete inhibition of p22(phox) mRNA expression by stable transfection of antisense p22(phox) cDNA into VSMCs results in a decrease in cytochrome b content, which is accompanied by a significant inhibition of angiotensin II-stimulated NADH/NADPH-dependent superoxide production, subsequent hydrogen peroxide production, and [3H]leucine incorporation. We provide the first evidence that p22(phox) is a critical component of superoxide-generating vascular NADH/NADPH oxidase and suggest a central role for this oxidase system in vascular hypertrophy.

            Author and article information

            Nephron Exp Nephrol
            Cardiorenal Medicine
            S. Karger AG
            April 1998
            20 March 1998
            : 6
            : 2
            : 112-120
            a Department of Medicine, Division of Nephrology and Osteology, and b Department of Pathology, University of Hamburg, University Hospital Eppendorf, Hamburg, Germany
            20513 Exp Nephrol 1998;6:112–120
            © 1998 S. Karger AG, Basel

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            Page count
            Figures: 6, Tables: 3, References: 37, Pages: 9
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            Original Paper

            Cardiovascular Medicine, Nephrology

            Irbesartan, Losartan, Angiotensin II, Anti-Thy 1 nephritis


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