Under control of the Ren-1(c) promoter, locally produced transforming growth factor-beta 1 induces accumulation of glomerular extracellular matrix intransgenic mice

Our purpose was to elucidate the hypothesis that paracrine-produced transfo rming growth factor (TGF)-beta 1. regulates the accumulation of extracellul ar matric: (ECM) in renal glomeruli, a hallmark of diabetic nephropathy, To produce TGP-beta 1 from the juxtaglomerular apparatus in mouse kidneys, wt cloned a mouse Ren-1(c) promoter fragment (-4.100 to +6 base pairs), upstr eam of porcine TGF-beta 1 (pTGF-beta 1) cDNA, mutated to ensure secretion o f biologically active TGF-beta 1. The resulting transgenic mice had signifi cantly more TGF-beta 1 in their kidneys than was in those of nontransgenic controls, as confirmed bf immunohistochemistry, and the production of TGF-b eta 1 was enhanced in vivo by captopril-induced stimulation of the Ren-1(c) promoter. Overproduction of pTGF-beta 1 close to the glomerulus resulted i n a local accumulation of ECM, composed partly of collagen type IV and lami nin, and thickening of the basement membrane, characteristic features of di abetic nephropathy, Interstitial accumulation of ECM and signs of tubular a trophy were present only In older mise (>5 months of age), Results from in situ hybridization and immunohistochemistry suggest that pTGF-beta 1 stimul ated the production of endogenous TGF-FI along collecting ducts and connect ing tubules. The increased amount of biologically active TGF-beta 1 transge nic as well as endogenous, was corroborated bg heightened proteoglycan synt hesis from incubated kidney slices, This transgenic model demonstrates that sustained local expression of TGF-beta 1 leads to glomerulopathy. We concl ude that autocrine- or paracrine-produced TGF-beta 1 may plas a role in the development of glomerular diseases, such as diabetic nephropathy.