Progressive loss of renal function is associated with glomerulosclerosis and also with interstitial fibrosis (1). Both of these abnormalities are characterized by the accumulation of extracellular matrix, and are believed to be almost exclusively irreversible.

Although several mechanisms have been suggested for extracellular matrix accumulation within the kidney, prevention and treatment of this abnormality have been mainly aimed at the block of action or activation of TGF, which is the main cytokine involved in matrix synthesis (2, 3, 4). In addition to the synthesis of matrix, accumulated matrix proteins can be the targets of therapy and may lead to the development of novel therapeutic approaches as will be discussed in this presentation.

Pirfenidone (PFD) is a new anti-fibrotic agent developed by Margolin S, Ph.D. (Marnac Inc., Dallas, TX, USA). Significant effects of this agent have been initially shown in experimental pulmonary fibrosis (5) and in peritoneal sclerosis (6). Negative tests of PFD toxicity suggest that this agent does not affect normal turnover of extracellular matrix.

Clinical trial of this agent has been already performed in patients with pulmonary fibrosis (7). As recently reported, PFD not only improved the survival rate, but also restored pulmonary function in patients with end-stage pulmonary fibrosis (8). Same kinds of results were also obtained in model animals (9). These data suggest that PFD not only prevents, but also may even reverse extracellular matrix accumulation.

We examined the efficacy of PFD on progressive renal disease in model rats made by monoclonal anti-Thy-1 antibody administration (10) and by partial nephrectomy (11). In these model rats, PFD not only prevented the progression of glomerular sclerotic lesions, but also ameliorated interstitial lesions and decreased collagen accumulation in the kidney. We also examined the effect of PFD in unilateral ureteral obstruction model rats, which is a well-characterized model of tubulointerstitial fibrosis. PFD not only attenuated interstitial changes and collagen accumulation, but also induced better recovery of renal function after release of obstruction (12). Thus, PFD is a promising agent for the prevention and treatment of interstitial fibrosis as well as glomerulosclerosis.

At the moment, the mechanisms of anti-fibrotic action of PFD are only partially understood. Suppression of increased TGF-Beta and its effects certainly is a possible mechanism as shown in remnant or post-obstructed kidney models (11, 12) as well as in models of pulmonary fibrosis (13). In addition, inhibition of PDGF_ has been also implicated in hamster model of lung fibrosis (14).

Inhibition of TNF-Alfa production by PFD shown in vitro may be another possible mechanism. TNF-Alfa is responsible for chronic inflammation, which precedes extracellular matrix accumulation. A recent report showed that PF D inhibited TNF-Alfa production after injection of lipopolysaccharides in rats and improved the survival rate after endotoxin shock (15). Furthermore, overexpression of TNF-Alfa in the lung resulted in pulmonary fibrosis, as recently reported (16). These mechanisms can explain, at least in part, the suppressive effects of PFD on matrix synthesis and accumulation. But, how can we explain the reversal of accumulated matrix as suggested in patients with end-stage pulmonary fibrosis?

A dynamic balance between synthesis and degradation determines amount of extracelluler matrix. Degradation of matrix protein is regulated by two major systems, i.e., matrix proteinase (MMP)/ tissue inhibitor of MMP (TIMP) system and plasminogen activator/plasmin system (17). It has been suggested in several models of renal disease that matrix accumulation is associated not only with enhanced synthesis, but also with suppression of MMP and/or activation of TIMP (18, 19). For the reversal of fibrosis, degradation of accumulated matrix should be enhanced by activation of MMP or suppression of TIMP, however, there is almost no drug available with such actions.

It may be very exciting to develop a new category of drug which activates matrix degrading system (20). Whether PFD belongs to this category of drug remains to be determined in future.

Further studies at cellular and molecular levels will certainly lead to the break-through to prevent and reverse this abnormality innear future. For an example, a specific gene (Fsp1) (21, 22) was recently cloned which triggers the transformation of tubular epithelial cells into myofibroblast (23) in response to cytokines, such as TGF-Beta. Transformation of epithelial cells or mesenchymal cells to active fiboblasts may be another potential target for the prevention of interstitial fibrosis in near future.

As a concluding remark, we should aim not only at prevention but also more at treatment of fibrosis because most of renal diseases are only recognized after the accumulation of extracellular matrix.

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