Podocyte-Specific Overexpression of the Antioxidant Metallothionein Reduces Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology Vol. 19; no. 11; pp. 2077 - 2085
• Main Authors: SHIRONG ZHENG, CARLSON, Edward C, LU YANG, KRALIK, Patricia M, YUN HUANG, EPSTEIN, Paul N
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.11.2008; American Society of Nephrology
• Subjects: Albuminuria - prevention & control; Animals; Antioxidants - metabolism; Apoptosis; Associated diseases and complications; Basic Research; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - etiology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic Nephropathies - prevention & control; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Gene Expression; Humans; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidneys; Medical sciences; Metallothionein - genetics; Metallothionein - metabolism; Mice; Mice, Transgenic; Nephrology. Urinary tract diseases; Oxidative Stress; Podocytes - metabolism; Podocytes - pathology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Urinary system involvement in other diseases. Miscellaneous; Endocrinopathy; Kidney disease; Nephrology; Urinary system disease; Diabetes mellitus; Gene overexpression; Antioxidant; Kidney; Urology; Renal glomerulus; Podocyte; Concomitant disease; Urinary system; Diabetic nephropathy; Metallothionein
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2007080967

Podocytes are critical components of the selective filtration barrier of the glomerulus and are susceptible to oxidative damage. For investigation of the role of oxidative stress and podocyte damage in diabetic nephropathy, transgenic mice that overexpress the antioxidant protein metallothionein (MT) specifically in podocytes (Nmt mice) were produced. MT expression was increased six- and 18-fold in glomeruli of two independent lines of Nmt mice, and podocyte-specific overexpression was confirmed. Glomerular morphology and urinary albumin excretion were normal in Nmt mice. OVE26 transgenic mice, a previously reported model of diabetic nephropathy, were crossed with Nmt mice to determine whether an antioxidant transgene targeted to podocytes could reduce diabetic nephropathy. Double-transgenic OVE26Nmt mice developed diabetes similar to OVE26 mice, but MT overexpression reduced podocyte damage, indicated by more podocytes, less glomerular cell death, and higher density of podocyte foot processes. In addition, expansion of glomerular and mesangial volume were significantly less in OVE26Nmt mice compared with OVE26 mice. Four-month-old OVE26Nmt mice had a 70 to 90% reduction in 24-h albumin excretion, but this protection does not seem to be permanent. These results provide evidence for the role of oxidative damage to the podocyte in diabetic mice and show that protection of the podocyte can reduce or delay primary features of diabetic nephropathy.