Role of TGF-ß in Mesangial Matrix Accumulation in Chronic Progressive Glomerular Disease

Lesions of focal segmental glomerulosclerosis (FSGS) are a pathological hallmark of progressive glomerular injury. Glomerulosclerosis frequently complicates most renal diseases, and is characterized by the collapse of the glomerular tuft with the accumulation of mesangial matrix. Transforming growth factor-ß (TGF-ß) is a key regulator of extracellular matrix (ECM) protein synthesis in renal cells. TGF-ß is secreted as latent complexes, which are stored in the ECM to provide stability to the active molecule and a readily activable source of it (Lawrence 2001). Overexpression of active TGF-ß1 in transgenic mice causes mesangial expansion and thickened capillary loops in the glomeruli (Kopp et al. 1996), while monoclonal antibody to TGF-ß reduces the glomerulosclerosis in experimental proliferative glomerulonephritis (GN) (Yu et al. 2004) and diabetic nephropathy (Benigni et al. 2003; Ziyadeh et al. 2000). Cultured mesangial cells secrete TGF-ß and ECM proteins in response to various fibrogenic stimuli (Kim et al. 2001; Lee et al. 2004; Lee and Song 2009a; Ziyadeh et al. 1994, 1998). In chronic mesangial diseases, such as IgA nephropathy (IgAN) and diabetic nephropathy, TGF-ß1 mRNA expression by mesangial cells is increased, yet mesangial immunostaining for active TGF-ß1 is frequently negative (Kim et al. 2002; Stein-Oakley et al. 1997; Wahab et al. 2005). Only podocytes covering the sclerotic segments exhibit increased expression of TGF-ß1 protein (Kim et al. 2002; Wahab et al. 2005). These findings suggest that mesangial cells secrete latent TGF-ß in chronic mesangial disease, which may be localized to the podocyte surface to be activated (Lee and Song 2009b). Podocytes are the target of injury in most glomerular diseases. Expression of TGF-ß mRNA and/or protein by podocytes is increased in progressive podocyte diseases, such as primary FSGS, membranous nephropathy, Alport syndrome and Denys-Drash syndrome (Kim et al. 2003; Kim et al. 1999; Patek et al. 2003; Sayers et al. 1999; Shankland et al. 1996). In addition, mesangial matrix is frequently increased in association with glomerulosclerosis (Gregory et al. 1996; Lee and Koh 1993; Lee and Lim 1995; Kim et al. 1995; Patek et al. 2003). Thus, TGFß, that is expressed and/or activated by podocytes, may contribute to mesangial matrix oversynthesis in both chronic mesangial disease and podocyte disease (Lee 2011). This review will discuss the recent findings on the mechanisms and consequences of latent TGF-ß activation and TGF-ß-induced mesangial matrix accumulation in chronic progressive glomerular disease.