Podocyte-specific overexpression of metallothionein mitigates diabetic complications in the glomerular filtration barrier and glomerular histoarchitecture: a transmission electron microscopy stereometric analysis

• Published in: Diabetes/metabolism research and reviews Vol. 29; no. 2; pp. 113 - 124
• Main Authors: Carlson, Edward C., Chhoun, Jennifer M., Laturnus, Donna I., Bikash, KC, Berg, Brittany, Zheng, Shirong, Epstein, Paul N.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2013; Wiley Subscription Services, Inc
• Subjects: Albuminuria - prevention & control; Animals; Diabetic Nephropathies - physiopathology; Diabetic Nephropathies - prevention & control; diabetic nephropathy; endothelial fenestrations; foot process width; Glomerular Basement Membrane - physiopathology; Glomerular Filtration Barrier - pathology; Glomerular Filtration Barrier - physiopathology; Kidney Glomerulus - pathology; Kidney Glomerulus - physiopathology; Metallothionein - biosynthesis; Metallothionein - genetics; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Oxidative stress; Podocytes - metabolism; Podocytes - pathology; TEM morphometry
• ISSN: 1520-7552; 1520-7560
• DOI: 10.1002/dmrr.2342

Background We previously demonstrated that cellular and extracellular components of the blood–urine barrier in renal glomeruli are susceptible to damage in OVE transgenic mice, a valuable model of human diabetic nephropathy that expresses profound albuminuria. Methods To test our hypothesis that glomerular filtration barrier damage in OVE mice may be the result of oxidative insult to podocytes, 150‐day‐old bi‐transgenic OVENmt diabetic mice that overexpress the antioxidant metallothionein specifically in podocytes were examined by enzyme‐linked immunosorbent assay for albuminuria mitigation and by unbiased transmission electron microscopy (TEM) stereometry for protection from chronic structural diabetic complications. Results Although blood glucose and HbA1c levels were indistinguishable in OVE and OVENmt animals, albuminuria was significantly reduced (average >7‐fold) in OVENmt mice through 8 months of age. Interestingly, the Nmt transgene provided significant glomerular protection against diabetic nephropathic complications outside of the podocyte. Glomerular filtration barrier damage was reduced in OVENmt mice, including significantly increased area occupied by endothelial luminal fenestrations (~13%), significantly reduced glomerular basement membrane (GBM) thickening (~17%) and significantly less podocyte effacement (~18%). In addition, OVENmt mice exhibited significantly reduced glomerular volume (~50%), fewer glomerular endothelial cells (~33%), fewer mesangial cells (~57%) and fewer total glomerular cells (~40%). Conclusions These results provide evidence of oxidative damage to podocytes induces primary diabetic nephropathic features including severe and sustained albuminuria, specific glomerular filtration barrier damage and alterations in glomerular endothelial and mesangial cell number. Importantly, these diabetic complications are significantly mitigated by podocyte targeted metallothionein overexpression. Copyright © 2012 John Wiley & Sons, Ltd.