Renoprotection from Diabetic Complications in OVE Transgenic Mice by Endothelial Cell Specific Overexpression of Metallothionein

Abstract

In an effort to test our working hypothesis that diabetes‐induced renal glomerular damage may be the result of oxidative insult, JTMT transgenic mice were produced that overexpress the antioxidant protein metallothionein specifically in endothelial cells. JTMT animals were crossed with severely diabetic OVE transgenic mice to determine whether an endothelial specific antioxidant transgene might provide renoprotection from chronic diabetic complications. In double transgenic 150 day‐old OVE‐JTMT mice, diabetic parameters including blood glucose and HbA1c were indistinguishable from age‐matched OVE mice. However, our data indicate that endothelial‐specific metallothionein overexpression in OVE‐JTMT mice reduced a number of nephropathic complications of diabetes including severe albuminuria. In addition, compared to OVE diabetic mice, double transgenic OVE‐JTMT animals showed significant protection to all major components of the glomerular filtration barrier (i.e. podocyte foot process effacement, glomerular basement membrane thickening, and endothelial damage as evidenced by reduced loss of percent area of glomerular luminal capillary endothelial fenestrations). Moreover, when compared to OVE diabetic animals, OVE‐JTMT mice showed reduced glomerular hypertrophy, lowered mesangial cell density and reduced total glomerular cytoproliferation. These results suggest a direct role of oxidative damage to endothelial cells and indicate that their targeted protection can reduce or delay several features of diabetic nephropathy.