Renoprotection From Diabetic Complications in OVE Transgenic Mice by Endothelial Cell Specific Overexpression of Metallothionein: A TEM Stereological Analysis

• Published in: Anatomical record (Hoboken, N.J. : 2007) Vol. 300; no. 3; pp. 560 - 576
• Main Authors: Carlson, Edward C., Chhoun, Jennifer M., Grove, Bryon D., Laturnus, Donna I., Zheng, Shirong, Epstein, Paul N., Tan, Yi
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2017; John Wiley and Sons Inc
• Subjects: Animals; Blood Glucose - metabolism; diabetic mice; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Disease Models, Animal; electron microscopy; Endothelial Cells - metabolism; Endothelial Cells - pathology; glomerular basement membrane; glomerular cells; glomerular filtration barrier; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Metallothionein - genetics; Metallothionein - metabolism; Mice; Mice, Transgenic; Oxidative Stress; Podocytes - metabolism; Podocytes - pathology; Renal Biology; glomerular cells; glomerular filtration barrier; electron microscopy; diabetic mice; glomerular basement membrane
• ISSN: 1932-8486; 1932-8494
• DOI: 10.1002/ar.23511

ABSTRACT We previously demonstrated that OVE transgenic diabetic mice are susceptible to chronic complications of diabetic nephropathy (DN) including substantial oxidative damage to the renal glomerular filtration barrier (GFB). Importantly, the damage was mitigated significantly by overexpression of the powerful antioxidant, metallothionein (MT) in podocytes. To test our hypothesis that GFB damage in OVE mice is the result of endothelial oxidative insult, a new JTMT transgenic mouse was designed in which MT overexpression was targeted specifically to endothelial cells. At 60 days of age, JTMT mice were crossed with age‐matched OVE diabetic mice to produce bi‐transgenic OVE‐JTMT diabetic progeny that carried the endothelial targeted JTMT transgene. Renal tissues from the OVE‐JTMT progeny were examined by unbiased TEM stereometry for possible GFB damage and other alterations from chronic complications of DN. In 150 day‐old OVE‐JTMT mice, blood glucose and HbA1c were indistinguishable from age‐matched OVE mice. However, endothelial‐specific MT overexpression in OVE‐JTMT mice mitigated several DN complications including significantly increased non‐fenestrated glomerular endothelial area, and elimination of glomerular basement membrane thickening. Significant renoprotection was also observed outside of endothelial cells, including reduced podocyte effacement, and increased podocyte and total glomerular cell densities. Moreover, when compared to OVE diabetic animals, OVE‐JTMT mice showed significant mitigation of nephromegaly, glomerular hypertrophy, increased mesangial cell numbers and increased total glomerular cell numbers. These results confirm the importance of oxidative stress to glomerular damage in DN, and show the central role of endothelial cell injury to the pathogenesis of chronic complications of diabetes. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:560–576, 2017. © 2016 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.