Fibrosis is a pathological process that results from some form of injury and can occur in any organ. When fibrosis develops it typically causes tissue dysfunction and organ failure. The biological cause of fibrosis is the accumulation of excessive amounts of extracellular matrix within a tissue. Fibrosis within glomeruli (glomerulosclerosis) and between tubules (tubulointerstitial fibro-sis) causes the progressive loss of renal function that leads to end-stage renal disease in humans with diabetes, glomerulonephritis or hypertension. It is now widely believed that fibrosis represents an excess of the normal repair process that follows tissue injury and, accordingly, fibrosis has been termed the" dark side" of tissue repair [1]. The idea that normal tissue repair and fibrogenesis are closely related is based on the overwhelming evidence that both involve similar biological processes that are regulated by the same group of molecules [2]. A prime example of this is the role of transforming growth factor-n (TGF-p). TGF-13 is a cytokine or signaling molecule whose potent fibrogenic properties are derived from its multiple actions in tissue repair [3, 4]. TGF-f3 is unique in its ability to stimulate strongly the deposition of extracellular matrix by four separate, simultaneous effects, as depicted in Figure 1. TGF-p acts directly to stimulate the synthesis of most matrix molecules including fibronectin, collagens and proteoglycans. At the same time, TGF-f3 blocks the degradation of matrix by inhibiting the secre-tion of proteases and inducing the production of protease inhibitors. TGF-f3 also modulates the expression of integrin matrix receptors on cells in a manner that facilitates cell-matrix adhesion and matrix deposition. Finally, TGF-/3 autoinduces its own production, which greatly amplifies its biological actions. These four fibrogenic effects of TGF-13 have been demonstrated independently in several types of cultured cells. However, in a model of acute glomerulonephritis, we have shown these TGF-13 effects as the cause of the rapid deposition of matrix in the injured glomeruli.

TGF-13 in acute glomerulonephritis The model of acute mesangial proliferative glomerulonephritis in the rat produced by a single injection of anti-thymocyte serum (ATS) is ideal to study the molecular events in fibrogenesis [5]. Mesangial cells, but not other glomerular cells, have a Thy-i-like antigen on their surface [6]. Injection of ATS causes a dose-and complement-dependent lysis of a portion of the mesangial cell population [7]. The injured mesangial cells serve as a stimulus to initiate the repair process, just as would occur following a knife wound in the skin. Thus, ATS-induced glomerulonephrits serves a dual purpose of providing biological insight into the basic mech-