TGFβ1, 2 and 3 mRNAs are weakly expressed in normal kidneys [15]. TGFβ1 protein expression in normal kidneys occurs in the glomerular basement membrane and in the mesangium. TGFβ1 mRNA expression occurs in glomerular cells [16].

TGFβ1 mRNA is enhanced in several glomerular diseases [16]. Renal diseases that are not characterised with increased extracellular membrane (ECM) proliferation like thin basement disease and minimal change disease, show the same pattern of TGFβ1 mRNA expression as normal kidneys [17].

Other renal diseases such as: diabetic nephropathy, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis and crescentic glomerulonephritis are featured by increased ECM in renal tissue [17]. Here TGFβ1, 2 and 3 mRNAs expression are increased in glomeruli and tubulo interstitium [17].

CAN is characterised by tubular atrophy, interstitial fibrosis and a variable degree of glomerulosclerosis. Some authors have measured intragraft expression of TGFβ1 mRNA, and they have found a significant association between TGFβ1 mRNA levels and renal allograft interstitial fibrosis [18].

The late consequences of diabetic nephropathy are glomerulosclerosis and loss of available filtration surface [19]. There is evidence that high glucose concentration induces TGFβ1 gene expression [19]. Studies in diabetic rats and non obese diabetic mice have shown that TGFβ 1 mRNA levels are elevated in cortical tubular cells [20].

Rats with protein overload have a progressive increase of TGFβ1 mRNA levels in the interstitium and in a lesser degree in cortical tubular cells [21].

In another rat model, fibrosis and interstitial inflammation were produced by a high cholesterol diet and there was significant expression of TGFβ1 mRNA in the renal cortex and interstitium [22].

TGFβ1 mRNA is also expressed in mesangial cells and in resident glomerular cells in rats with Masugi nephritis [23].

The TGFβ1 protein is a homodimer that has a molecular weight of 25 Kδa [25]. Cells secrete TGFβ as a protein complex that is made of three proteins, the mature TGFβ dimer, the TGFβ propeptide dimer or latency associated peptide (LAP), and the latent TGFβ binding protein (LTBP). When mature TGFβ and LAP are separated, TGFβ is activated [25].

TGFβ is a broad-spectrum regulatory cytokine with involvement in embryogenesis, growth, tissue repair and immunological processes [25]. The regulatory properties of TGFβ are in many instances produced by influencing gene expression of other molecules like collagen, fibronectin, tenascin, plasminogen activator inhibitor (PAI-1), and enzymes that inhibit ECM [25].

Most human cells have TGFβ receptors [25] and there are three different types of TGFβ receptors. TGFβ receptors are cell surface proteins. Only receptors II and I are involved in signal transduction. When TGFβ binds to type II receptor, the type I receptor is recruited and phosphorylated to produce a heterodimeric complex that activates signalling pathways [26]. The type III receptor modulates ligand access to the signalling receptors. Receptor I needs receptor II for ligand binding. TGFβ binds first to receptor II and this interaction makes receptor I to be incorporated into the complex and this starts signalling [27]. Type III receptor is a transmembrane proteoglycane and its role is to allow high affinity binding between TGFβ and TGFβ receptor II.

The activity of some growth factors is controlled by their molecules being produced initially in an inactive state requiring downstream activation. Without latency, cytokines would produce their effects before reaching their target cells [28].

The precursor molecule is cleaved in the Golgi apparatus at position 279 after a di-arginine motif by a furin-type protease [28]. The TGFβ propeptide and mature TGFβ are united noncovalently forming a latent complex from which TGFβ must be released to be able to elicit its biological activity. Latency is a critical step in the control of TGFβ activity because TGFβ expression does not always correlate with increased levels of active TGFβ [29]. Latency also regulates TGFβ bioavailability and therefore modulates its function.

Latent TGFβ activation can occur by direct interaction with Thrombospondin-1 (TSP-1). TSP-1 is an adhesive protein that binds to cell surfaces and extracellular matrix.

Mature TGFβ binds to TSP-1 forming a complex in which TGFβ remains active [28].

When TGFβ interacts with cell receptors the signal is transmitted to intracellular signalling cytoplasmic proteins known as Smads. These signalling proteins are transported rapidly into the nucleus and they are able to activate and inhibit functions that mediate the biological effects of TGFβ [30].

TGFβ has a paramount role in healing and tissue repair. An appropriate balance between extracellular matrix protein synthesis and degradation is essential for growth and healing. Protein degradation is catalysed by several enzymes including plasmin and matrix metalloproteinases (MMP) [31]. When this balance is disturbed fibrosis may result. TGFβ regulates the synthesis of extracellular matrix proteins such as collagen, fibronectin and matrix proteoglycans (Fig. 2). TGFβ is also able to inhibit extracellular matrix degradation by inhibiting plasmin and MMPs [31]. Experiments in animal lung models demonstrate that TGFβ is a potent fibrogenic cytokine that initiates a local fibrotic response that is subsequently perpetuated despite the absence of continued TGFβ expression [31]. In normal kidney tissue, TGFβ mRNA expression is low. However, in proliferative glomerular diseases like mesangial proliferative glomerulonephritis and focal segmental glomerulosclerosis there is excessive regulation of TGFβ. Other non-proliferative glomerular diseases have no increased expression of TGFβ [31]. Several animal models have demonstrated an association between glomerular expression of TGFβ and fibrosis [31]. Border and colleagues used neutralising anti-TGFβ antibody in a rat model of proliferative glomerulonephritis and they were able to show improvement in the glomerular histology [32].

In diabetic nephropathy there is loss of glomerular filtration surface due to glomerulosclerosis and mesangial expansion. Some animal experiments have shown that hyperglycaemia modulates TGFβ gene expression and this effect may be produced in association with other cytokines like IL-1 and platelet derived growth factor (PDGF) [31]. Furthermore, diabetic patients have higher circulating levels and urinary levels of TGFβ than the normal population [31].

Chronic glomerular disease eventually induces interstitial fibrosis and, conversely, chronic interstitial disease may lead to glomerulosclerosis. In renal fibrosis there is an interstitial chronic inflammatory cell infiltrate with proliferation of interstitial myofibroblasts that is cytokine driven [33]. Furthermore, in situations of renal injury, epithelial cells in the kidney may transform into fibroblasts by the process known as epithelial-mesenchymal transdifferentiation [34]. TGFβ and other growth factors and adhesion molecules are involved in this process. The release of TGFβ into the renal interstitium may be produced by renal parenchyma and /or infiltrating monocytes or lymphocytes [31].

The Angiotensin II (AII) interaction with TGFβ has important consequences for renal fibrosis. AII has haemodynamic properties but is also able to act as a growth factor stimulating renal and cardiac cell hypertrophy and increasing expression of type IV collagen mRNA and TGFβ synthesis by cells. Furthermore, administration of anti-TGFβ antibody is able to block the effect of AII on matrix protein synthesis [31]. Experimental models of renal fibrosis based on neutralizing the effects of AII have shown decreased expression of TGFβ [35-37].