Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice.
Transgenic mice overexpressing a constitutively active human TGF-beta1 under control of the rat phosphoenolpyruvate carboxykinase regulatory sequences developed fibrosis of the liver, kidney, and adipose tissue, and exhibited a severe reduction in body fat. Expression of the transgene in hepatocytes resulted in increased collagen deposition, altered lobular organization, increased hepatocyte turnover, and in extreme cases, hemorrhage and thrombosis. Renal expression of the transgene was localized to the proximal tubule epithelium, and was associated with tubulointerstitial fibrosis, characterized by excessive collagen deposition and increased fibronectin and plasminogen activator inhibitor-1 immunoreactivity. Pronounced glomerulosclerosis was evident, and hydronephrosis developed with low penetrance. Expression of TGF-beta1 in white and brown adipose tissue resulted in a lipodystrophy-like syndrome. All white fat depots and brown fat pads were severely reduced in size, and exhibited prominent fibroplasia. This reduction in WAT was due to impaired adipose accretion. Introduction of the transgene into the ob/ob background suppressed the obesity characteristic of this mutation; however, transgenic mutant mice developed severe hepato- and splenomegaly. These studies strengthen the link between TGF-beta1 expression and fibrotic disease, and demonstrate the potency of TGF-beta1 in modulating mesenchymal cell differentiation in vivo.
Clouthier
D E
DE
Department of Biochemistry and the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050, USA.
Comerford
S A
SA
Hammer
R E
RE
D000273:Adipose Tissue / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008060:Lipodystrophy / Q000209:etiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013577:Syndrome; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D004247:DNA; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)