Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury.
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.
Matsusaka
Taiji
T
Department of Pediatrics, Vanderbilt University School of Medicine, 1161 21st Avenue South, MCN C4204, Nashville, TN 37232-2584, USA. taiji.matsusaka@vanderbilt.edu
Xin
Jing
J
Niwa
Suguri
S
Kobayashi
Kazuto
K
Akatsuka
Akira
A
Hashizume
Hiroomi
H
Wang
Qing-Cheng
QC
Pastan
Ira
I
Fogo
Agnes B
AB
Ichikawa
Iekuni
I
D000818:Animals; D000911:Antibodies, Monoclonal; D004195:Disease Models, Animal; D005098:Exotoxins; D005818:Genetic Engineering; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D000922:Immunotoxins; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D009404:Nephrotic Syndrome / Q000139:chemically induced; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D012720:Severity of Illness Index
D000911:Antibodies, Monoclonal; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; D000922:Immunotoxins; D015375:Receptors, Interleukin-2