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      Accelerated Glomerular Injury in Hemi-Nephrectomized Transgenic Mice of Mesangial Cell-Predominant Serpin, Megsin

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          Mesangial cells play a critical role in the maintenance of normal glomerular functions such as matrix remodeling and immune complex disposal. We recently identified a novel human mesangium-predominant gene, megsin, which is a new member of the serine protease inhibitor (serpin) superfamily. While our previous studies demonstrated progressive mesangial matrix expansion and an increase in the number of mesangial cells in megsin transgenic mice, it took 40 weeks to develop these manifestations. Here we performed hemi-nephrectomy to accelerate glomerular injury in megsin transgenic mice. Hemi-nephrectomized transgenic mice developed focal segmental mesangial expansion, which was associated with proteinuria. Megsin has thus a biologically relevant influence on the development of glomerular damage. The hemi-nephrectomized model of this transgenic mouse might serve as a tool to investigate the mechanisms of glomerular disease.

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          Cloning of rodent megsin revealed its up-regulation in mesangioproliferative nephritis.

          We recently cloned a new human mesangium-predominant gene, megsin. Megsin is a novel member of the serine protease inhibitor (serpin) superfamily. To elucidate functional roles of this gene, we cloned megsin in rodents and investigated its role in a rat nephritis model.
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            Heminephrectomy Causes the Progression of Glomerulosclerosis and Apoptosis in High IgA Strain ddY Mice

            Background: The reduction in nephrons in IgA nephropathy is critical to the prognosis of this disease. However, the immunopathological mechanism of the modifications seen in glomerular lesions is not clear. We thus investigated the influence of nephron reduction by heminephrectomy on renal lesions in a high immunoglobulin A inbred strain of ddY mouse (HIGA mouse), which shows progressive mesangial sclerosis with elevated renal expression of transforming growth factor (TGF)-β. Methods: Five-week-old HIGA mice were heminephrectomized (Nx), and were evaluated in comparison with a sham-operated group (S) at 40 weeks old. Histological findings, immunoglobulin depositions (IgG, IgA, and IgM), and expressions of cytokine and extracellular matrix proteins (TGF-β, fibronectin, collagen type I and IV) were analysed. PCNA and TUNEL stainings were performed with electron microscopic detection of apoptosis. Tissue renin-angiotensin systems (RAS) were also investigated by real-time quantitative RT-PCR. Results: In the Nx group, the glomerular tuft area and ratio of mesangial matrix area per tuft were significantly increased, and the glomerular cell count per tuft area was significantly decreased. Glomerular immunoglobulin deposits of IgG, IgA, and IgM in Nx were all significantly expanded in the paramesangium. The glomerular expressions of TGF-β and the extracellular matrix proteins were significantly increased in Nx mice. In contrast to the significant decrease of PCNA-positive cells, TUNEL-positive cells were significantly increased in Nx. Angiotensin-converting enzyme (ACE) was significantly increased in the renal cortex of Nx. Conclusion: Simple heminephrectomy, other than 5/6 renal ablation, of HIGA mice may be a potential model for research into the progressive glomerulosclerosis of human IgA nephropathy. The pathological role of apoptosis is apparently involved in these disease processes, possibly through upregulated RAS.
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              Specific tissue distribution of megsin, a novel serpin, in the glomerulus and its up-regulation in IgA nephropathy.

              Mesangial cells play critical roles in maintaining a structure and function of the glomerulus. We previously cloned a novel mesangium-predominant gene, megsin, a new serine protease inhibitor. To clarify localization and roles of megsin protein, we raised polyclonal antibodies to megsin. By immunohistochemistry, megsin protein was specifically identified in the mesangial area. The amount of megsin protein was increased in glomeruli of patients with IgA nephropathy than in those of normal individuals and of patients with minimal change nephrotic syndrome or membranous nephropathy, suggesting a pathophysiological role of megsin as a functional modulator of mesangial functions in situ.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 2004
                17 November 2004
                : 96
                : 4
                : e127-e133
                aPreventure Program, Office of Technology Transfer, Japan Science and Technology Cooperation, Tokyo, bInstitute of Medical Sciences and Department of Medicine, Tokai University School of Medicine, Kanagawa, and cDivision of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan
                77379 Nephron Exp Nephrol 2004;96:e127–e133
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 24, Pages: 1
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                Original Paper

                Cardiovascular Medicine, Nephrology

                Serpin, IgG deposition, Mesangial expansion, Hemi-nephrectomy


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