TRANSGENIC MICE WITH INCREASED PLASMA-LEVELS OF TGF-BETA-1 DEVELOP PROGRESSIVE RENAL-DISEASE

Several lines of evidence suggest that local production of transformin g growth factor-beta (TGF-beta) contributes to renal disease, particul arly to the accumulation of the extracellular matrix protein that char acterizes glomerulosclerosis and interstitial fibrosis. We have examin ed whether elevated levels of circulating TGF-beta adversely affect th e kidney. We have studied mice that are transgenic for an active form of TGF-beta 1 under the control of murine albumin promoter and enhance r DNA sequences. These mice express the transgene exclusively in the l iver and have elevated plasma concentrations of TGF-beta 1. Renal dise ase was seen in two of three lines of Alb/TGF-beta 1 transgenic mice; these two lines had the highest levels of hepatic transgene expression and the highest plasma TGF-beta 1 levels. Histologic abnormalities, w hich included mesangial expansion and thickened capillary loops, were noted in the glomeruli by 3 weeks of age. Interstitial fibrosis and tu bular atrophy appeared subsequently. Mice from Line 25, the line with highest levels of TGF-beta 1, developed proteinuria by 5 weeks of age. These mice subsequently manifested nephrotic syndrome with ascites an d progressive azotemia; uremic death occurred in more than 25% of the mice by 15 weeks of age. The glomeruli contained immune deposits in su bendothelial and mesangial locations, but complement deposition was in frequent. Ultrastructural examination revealed an increase in extracel lular matrix material, including collagen fibrils, in subendothelial a nd mesangial locations. Increased levels of circulating TGF-beta 1 ind uced progressive renal disease that was characterized by mesangial exp ansion, 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-beta 1 in duce progressive glomerulosclerosis.