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A Severe Diabetic Nephropathy Model With Early Development of Nodule-Like Lesions Induced by Megsin Overexpression in RAGE/iNOS Transgenic Mice

¹ Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Kanagawa, Japan
² Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
³ Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan
⁴ Department of Anatomy, Fujita Health University School of Medicine, Aichi, Japan
⁵ Department of Advanced Biological Sciences for Regeneration, Tohoku University Graduate School of Medicine, Miyagi, Japan
⁶ Service de Nephrologie, Universite Catholique de Louvain, Brussels, Belgium

Address correspondence and reprint requests to Toshio Miyata, MD, PhD, Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. E-mail: t-miyata{at}is.icc.u-tokai.ac.jp

Key Words: AGE, advanced glycation end product • CML, carboxymethyllysine • ELISA, enzyme-linked immunosorbent assay • iNOS, inducible nitric oxide synthase • 8-OHdG, 8-hydroxy-deoxyguanosine • PAM, periodic acid–methenamine silver • PAS, periodic acid Schiff • RAGE, receptor for advanced glycation end products • -SMA, -smooth muscle actin

Many factors are involved in the pathogenesis of diabetic nephropathy. A single gene abnormality may be prerequisite but insufficient to the disease to manifest. It is therefore only when a second or sometimes a third damage is associated that the consequences of pathogenic phenotypes become evident. We generated the triple transgenic mice overexpressing megsin (a novel glomerular-specific serpin), a receptor for advanced glycation end products (RAGE), and inducible nitric oxide synthase (iNOS). Compared with the single- or two-gene transgenic mice, the triple transgenic mice developed, at an early age (16 weeks), severe albuminuria and renal damage with all of the characteristics of human diabetic nephropathy (i.e., glomerular hypertrophy, diffuse mesangial expansion, inflammatory cell infiltration, and interstitial fibrosis). Interestingly, 30–40% of glomeruli exhibit nodule-like lesions. Oxidative and carbonyl stress makers (pentosidine, N-carboxymethyllysine, and 8-hydroxy-deoxyguanosine) were significantly higher in the triple transgenic mice. The iNOS transgenic mice have a diabetes phenotype, the renal consequences of which are moot, and the superimposition of RAGE leads to more conspicuous manifestations. By additional overexpression of megsin, a gene known to be involved in mesangial proliferation and expansion, these local consequences become dramatically manifest and approximate those observed in human pathology. This multiple hit approach is of interest in consideration of the sequential events during development of diabetic nephropathy.

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