Transforming growth factor-p (TGF-P) stimulates the accumulation of extracellular matrix in renal and hepatic disease. Kidney glornerular mesangial cells (GMC) and liver fat-storing cells (FSC) produce latent or inactive TGF-P. In this study, we characterized the latent TGF-P complexes secreted by these cells. Human FSC produce a single latent TGF-P complex, predominantly of the TGF-P1 isoform, whereas GMC secrete multiple complexes of latent TGF-P, containing P1 and P2 isoforms. At least four forms were identified in GMC using ion exchange chromatography, including a peak not previously described in other cell types which eluted at 0.12 M NaCI, and predominantly of the P2 isoform. Both cell types secrete the latent TGF-01 binding protein of 190 kDa, as part of a high molecular weight TGF-P complex. Epidermal growth factor stimulates the secretion of latent TGF-j3 and latent TGF-P binding protein in both cell types. Secretion of the latent TGF-P in both cell types was found to be associated with secretion of decorin. This study shows that vascular pericytes from the kidney and the liver have distinctly different profiles of latent TGF-P complexes, with GMC secreting a unique form of latent TGF-P2. The regulatory effect of epidermal growth factor and platelet-derived growth factor has potential implication for the pathophysiology of liver regeneration and chronic liver and kidney diseases. o 1996 WiIey-Liss, Inc.
Chronic renal and hepatic diseases are characterized by the expansion of fibrillar and non-fibrillar extracellular matrix, resulting in the disruption of the normal architecture and function of these organs. Extensive in vivo and in vitro investigation has shown that transforming growth factor-P (TGF-p) plays a key role in the pathogenesis of tissue fibrosis (Border and Ruoslahti, 1992). TGF-P induces the accumulation of extracellular matrix in several tissues, including liver and kidney, by stimulation of matrix production and inhibition of matrix degradation (Massague, 1990). During chronic renal and hepatic injury, cellular targets for the actions of TGF-P include glomerular mesangial cells (GMC) as well as liver fat-storing cells (FSC), also referred to as Ito cells or lipocytes (Weiner et al., 1994;Bruijn et al., 1994). Mesangial cells and FSC share several properties. Both cell types are of mesenchymal origin, contract in response to agonists, and are localized in close proximity to the endothelial lining of capillary networks. Owing to similarities with cell types in other microvascular beds, GMC and FSC are referred to as vascular pericytes.
GMC and FSC not only respond to TGF-P, but are also a source of this cytokine (Davis et al., 1990;Kaname et al., 1992). Similar to many other cell types, they secrete TGF-P in the extracellular space in an "inactive" or 'latent" form (Lawrence et al., 1985;Pircher et al., 1986). The "active" or "mature" form of 0 1996 WILEY-LISS, INC.
TGF-P consists of a homodimer of 25 kDa. In the latent form the mature peptide 25 kDa homodimer is noncovalently associated with the 75 kDa latency associated peptide, or precursor. The molecular mass of this latent TGF-P complex is approximately 100 kDa (Gentry et al., 1987; Bonewald et al., 1991). The latent form of TGF-P1 may be secreted in a larger complex covalently bound to a protein referred to as latent TGF-P1 binding protein (LTBP) (Wakefield et al., 1987(Wakefield et al., , 1989;;Miyazono et al., 1991). This protein exists in at least two forms: a 180-195 kDa form that is secreted by fibroblasts, or a truncated form of approximately 135-160 kDa that is secreted by platelets (Kanzaki et al., 1990). Recent studies suggest that the LTBP is involved in the assembly and possibly the activation of latent TGF-P1 (Miyazono et al., 1991; Flaumenhaft et al., 19931, and also in its binding to the extracellular matrix (Taipale et al., 1994).
Multiple forms of latent TGF-P are secreted by differ-