Several lines of evidence suggest that local production of transforming growth factor-β (TGF-β) contributes to renal disease, particularly to the accumulation of the extracellular matrix protein that characterizes glomerulosclerosis and interstitial fibrosis. We have examined whether elevated levels of circulating TGF-β adversely affect the kidney. We have studied mice that are transgenic for an active form of TGF-β1 under the control of murine albumin promoter and enhancer DNA sequences. These mice express the transgene exclusively in the liver and have elevated plasma concentrations of TGF-β1. Renal disease was seen in two of three lines of Alb/TGF-β1 transgenic mice; these two lines had the highest levels of hepatic transgene expression and the highest plasma TGF-β1 levels. Histologic abnormalities, which included mesangial expansion and thickened capillary loops, were noted in the glomeruli by 3 weeks of age. Interstitial fibrosis and tubular atrophy appeared subsequently. Mice from Line 25, the line with highest levels of TGF-β1, developed proteinuria by 5 weeks of age. These mice subsequently manifested nephrotic syndrome with ascites and progressive azotemia; uremic death occurred in more than 25% of the mice by 15 weeks of age. The glomeruli contained immune deposits in subendothelial and mesangial locations, but complement deposition was infrequent. Ultrastructural examination revealed an increase in extracellular matrix material, including collagen fibrils, in subendothelial and mesangial locations. Increased levels of circulating TGF-β1 induced progressive renal disease that was characterized by mesangial expansion, accumulation of glomerular immune deposits and matrix proteins, and interstitial fibrosis in this transgenic mouse model. These data suggest that chronically elevated circulating levels of TGF-β1 induce progressive glomerulosclerosis.
|Number of pages||13|
|Publication status||Published - jún. 1 1996|
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Molecular Biology
- Cell Biology