A new mouse model for renal lesions produced by intravenous injection of diphtheria toxin A-chain expression plasmid.
BACKGROUND
Various animal models of renal failure have been produced and used to investigate mechanisms underlying renal disease and develop therapeutic drugs. Most methods available to produce such models appear to involve subtotal nephrectomy or intravenous administration of antibodies raised against basement membrane of glomeruli. In this study, we developed a novel method to produce mouse models of renal failure by intravenous injection of a plasmid carrying a toxic gene such as diphtheria toxin A-chain (DT-A) gene. DT-A is known to kill cells by inhibiting protein synthesis.


METHODS
An expression plasmid carrying the cytomegalovirus enhancer/chicken beta-actin promoter linked to a DT-A gene was mixed with lipid (FuGENE trade mark 6) and the resulting complexes were intravenously injected into adult male B6C3F1 mice every day for up to 6 days. After final injection, the kidneys of these mice were sampled on day 4 and weeks 3 and 5.


RESULTS
H-E staining of the kidney specimens sampled on day 4 revealed remarkable alterations in glomerular compartments, as exemplified by mesangial cell proliferation and formation of extensive deposits in glomerular basement membrane. At weeks 3 and 5, gradual recovery of these tissues was observed. These mice exhibited proteinuria and disease resembling sub-acute glomerulonephritis.


CONCLUSIONS
Repeated intravenous injections of DT-A expression plasmid DNA/lipid complex caused temporary abnormalities mainly in glomeruli of mouse kidney. The disease in these mice resembles sub-acute glomerulonephritis. These DT-A gene-incorporated mice will be useful as animal models in the fields of nephrology and regenerative medicine.
Nakamura
Shingo
S
Division of Moleculer Nephrology and Bioartificial Organs, The Institute of Medical Sciences, Tokai University, Bohseidai, Isehara, Kanagawa 259-1193, Japan. snaka@me.ndmc.ac.jp
Terashima
Masuo
M
Kikuchi
Natsuko
N
Kimura
Minoru
M
Maehara
Tadaaki
T
Saito
Akira
A
Sato
Masahiro
M
D000199:Actins / Q000235:genetics; D000818:Animals; D002645:Chickens; D003433:Crosses, Genetic; D004167:Diphtheria Toxin / Q000235:genetics / Q000633:toxicity*; D004195:Disease Models, Animal; D015870:Gene Expression; D005813:Genes, Synthetic; D005822:Genetic Vectors / Q000008:administration & dosage / Q000633:toxicity; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D007275:Injections, Intravenous; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000473:pathology; D008055:Lipids; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000235:genetics / Q000633:toxicity*; D010957:Plasmids / Q000008:administration & dosage / Q000633:toxicity; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000633:toxicity*; D014162:Transfection
D000199:Actins; D004167:Diphtheria Toxin; C411955:FuGene; D008055:Lipids; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; C029795:diphtheria toxin fragment A