A severe diabetic nephropathy model with early development of nodule-like lesions induced by megsin overexpression in RAGE/iNOS transgenic mice.

@article{citeulike:2570895, abstract = {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(epsilon)-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.}, address = {Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Isehara, Kanagawa, Japan.}, author = {Inagi, R. and Yamamoto, Y. and Nangaku, M. and Usuda, N. and Okamato, H. and Kurokawa, K. and van Ypersele de Strihou, C. and Yamamoto, H. and Miyata, T. }, citeulike-article-id = {2570895}, issn = {0012-1797}, journal = {Diabetes}, month = {February}, number = {2}, pages = {356--366}, posted-at = {2008-03-22 01:10:33}, priority = {2}, title = {A severe diabetic nephropathy model with early development of nodule-like lesions induced by megsin overexpression in RAGE/iNOS transgenic mice.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/16443768}, volume = {55}, year = {2006} }

TY - JOUR ID - citeulike:2570895 L3 - citeulike-article-id:2570895 TI - A severe diabetic nephropathy model with early development of nodule-like lesions induced by megsin overexpression in RAGE/iNOS transgenic mice. JF - Diabetes VL - 55 IS - 2 SP - 356 EP - 366 AD - Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Isehara, Kanagawa, Japan. SN - 0012-1797 N2 - 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(epsilon)-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. AU - Inagi, R AU - Yamamoto, Y AU - Nangaku, M AU - Usuda, N AU - Okamato, H AU - Kurokawa, K AU - van Ypersele de Strihou, C AU - Yamamoto, H AU - Miyata, T PY - 2006/02// UR - http://view.ncbi.nlm.nih.gov/pubmed/16443768 ER -