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Genetic Engineering of Glomerular Sclerosis in the Mouse via Control of Onset and Severity of Podocyte-Specific Injury

Taiji Matsusaka^*,, Jing Xin^||, Suguri Niwa^¶, Kazuto Kobayashi, Akira Akatsuka^**, Hiroomi Hashizume, Qing-cheng Wang, Ira Pastan, Agnes B. Fogo^*,, and Iekuni Ichikawa^*,,||

Departments of ^* Pediatrics, Medicine, and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee; Institute of Medical Science, ^|| Department of Pediatrics, ^¶ Center of Excellence, and ^** Educational and Research Support Center, Tokai University Medical School, Isehara, Kanagawa, Japan; Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan; Department of Pediatrics, National Defense Medical College, Saitama, Japan; and Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Address correspondence to: Dr. Taiji Matsusaka, Department of Pediatrics, Vanderbilt University School of Medicine, 1161 21st Avenue South, MCN C4204, Nashville, TN 37232-2584. Phoen: 615-322-7416; Fax: 615-343-0110; taiji.matsusaka{at}vanderbilt.edu

Received for publication August 31, 2004. Accepted for publication January 6, 2005.

This study aimed to generate a mouse model of acquired glomerular sclerosis. A model system that allows induction of podocyte injury in a manner in which onset and severity can be controlled was designed. A transgenic mouse strain (NEP25) that expresses human CD25 selectively in podocytes was first generated. Injection of anti-Tac (Fv)-PE38 (LMB2), an immunotoxin with specific binding to human CD25, induced progressive nonselective proteinuria, ascites, and edema in NEP25 mice. Podocytes showed foot process effacement, vacuolar degeneration, detachment and downregulation of synaptopodin, WT-1, nephrin, and podocalyxin. Mesangial cells showed matrix expansion, increased collagen, mesangiolysis, and, later, sclerosis. Parietal epithelial cells showed vacuolar degeneration and proliferation, whereas endothelial cells were swollen. The severity of the glomerular injury was LMB2 dose dependent. With 1.25 ng/g body wt or more, NEP25 mice developed progressive glomerular damage and died within 2 wk. With 0.625 ng/g body wt of LMB2, NEP25 mice survived >4 wk and developed focal segmental glomerular sclerosis. Thus, the study has established a mouse model of acquired progressive glomerular sclerosis in which onset and severity can be preprogrammed by experimental maneuvers.

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