Zheng Shirong, Carlson Edward C, Yang Lu, Kralik Patricia M, Huang Yun, Epstein Paul N
Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
J Am Soc Nephrol. 2008 Nov;19(11):2077-85. doi: 10.1681/ASN.2007080967. Epub 2008 Jul 16.
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.
足细胞是肾小球选择性滤过屏障的关键组成部分，易受氧化损伤。为了研究氧化应激和足细胞损伤在糖尿病肾病中的作用，制备了在足细胞中特异性过表达抗氧化蛋白金属硫蛋白（MT）的转基因小鼠（Nmt小鼠）。在两个独立品系的Nmt小鼠的肾小球中，MT表达增加了6倍和18倍，并证实了足细胞特异性过表达。Nmt小鼠的肾小球形态和尿白蛋白排泄正常。将OVE26转基因小鼠（一种先前报道的糖尿病肾病模型）与Nmt小鼠杂交，以确定靶向足细胞的抗氧化转基因是否可以减轻糖尿病肾病。双转基因OVE26Nmt小鼠与OVE26小鼠一样患糖尿病，但MT过表达减少了足细胞损伤，表现为足细胞增多、肾小球细胞死亡减少以及足细胞足突密度增加。此外，与OVE26小鼠相比，OVE26Nmt小鼠的肾小球和系膜体积增大明显较少。4个月大的OVE26Nmt小鼠24小时白蛋白排泄减少了70%至90%，但这种保护作用似乎不是永久性的。这些结果为糖尿病小鼠中足细胞氧化损伤的作用提供了证据，并表明保护足细胞可以减少或延缓糖尿病肾病的主要特征。
