Chronic progressive interstitial fibrosis in renal disease—are there novel pharmacological approaches?

Masafumi Fukagawa, Masakuni Noda, Toshikatsu Shimizu and Kiyoshi Kurokawa

Tokyo Teishin Hospital, Tokyo, Pharmaceutical Research Division, Takeda Chemical Industries Ltd, Osaka; Shionogi Research Laboratories, Osaka and Tokai University, Kanagawa, Japan

Correspondence and offprint requests to: Masafumi Fukagawa MD PhD, Division of Nephrology and Clinical Research Center, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan.

Introduction

Progressive loss of renal function is associated not only with development of glomerulosclerosis, but also with that of interstitial fibrosis. Interstitial fibrosis is characterized by the destruction of renal tubules and interstitial capillaries as well as by the accumulation of extracellular matrix proteins. The severity of tubulointerstitial fibrosis has long been considered as a crucial determinant of progressive renal injury in both human and experimental glomerulonephritis. Moreover, previous studies have shown that decrease in glomerular filtration rate is better correlated with tubulointerstitial injury than with glomerulosclerosis [1,2].

Many studies have been published on the mechanisms and treatment of glomerulosclerosis. In contrast, the pathogenesis of interstitial fibrosis has been less well understood. The mechanisms that contribute to these two types of matrix accumulation in the kidney are in part common, but to some extent also different.

In this brief editorial, we focus on some new approaches to interstitial fibrosis that have recently helped to elucidate its pathogenesis.

New roles of the renin–angiotensin system in the development of interstitial fibrosis

Recent reports suggest that angiotensin II (AII) plays important roles in the development and amelioration of interstitial fibrosis through different types of AII receptors. AII not only contributes to glomerular capillary hypertension and an impairment of glomerular permselectivity, but influences also directly some functions of interstitial fibroblasts and tubular epithelial cells [3,4]. To date, molecular cloning and pharmacological studies have defined two major classes of AII receptors, i.e. AT1 and AT2 receptors. Most known effects of AII are mediated by AT1 receptors [5,6].

AT1 receptor antagonists improve capillary hypertension of the glomerulus via reduction of glomerular efferent arteriolar tone. Thus they interfere with the development of glomerular injury and proteinuria [3]. In addition, disturbed glomerular barrier function secondary to activation of AT1 receptor by AII permits proteins to escape into the urinary space and to exert toxic effects upon tubular epithelial cells [1,7]. Immune responses of tubular epithelial cells are induced by exposure to proteins, e.g. stimulation of the release of various cytokines, including transforming growth factor-ß1 (TGF-ß1) [1]. The release of such cytokines causes differentiation of interstitial fibroblasts (and possibly tubular epithelial cells) into myofibroblasts. This change of phenotype is characterized by de novo expression of alpha-smooth-muscle actin [8]. Recently, a specific gene (Fsp1) [9,10] was cloned, which triggers the transformation of tubular epithelial cells into myofibroblasts [11] in response to cytokines, such as TGF-ß. Furthermore, it has been shown that AII directly induced the expression of TGF-ß in cultured renal tubular cells and in fibroblasts [12]. Taken together, the activation of AT1 receptors in glomeruli, tubular epithelial cells and interstitial fibroblasts might be involved in the progression of interstitial fibrosis.

In the rat remnant kidney model, an AT1 receptor antagonist, candesartan cilexetil (TCV-116), was superior in preventing interstitial fibrosis and glomerulosclerosis compared to angiotensin-converting enzyme inhibitor (ACI) [13]. The beneficial effects of AT1 receptor antagonist were initially thought to be mediated mainly by the blockade of AT1 receptors.

In contrast to the AT1 receptor, much less is known about the functional properties of AT2 receptor. Since AT2 receptor expression is high in embryonic tissues and declines dramatically after birth [14], it was postulated that the AT2 receptor played a role in cell growth and differentiation. In contrast, recent reports suggested that AT2 receptors mediate antiproliferative effects and participate in cell apoptosis [5,6]. Since AII exhibits growth promoting properties via AT1 receptor in some cell types, AT1 and AT2 receptors might mediate counterbalancing signals [15]. A similar reciprocal relationship is also suggested with respect to vasoconstriction [16].

Interestingly, obstructed kidneys in AT2 receptor null mutant mice showed more severe interstitial fibrosis, including decreased apoptosis and increased cellularity and collagen deposition compared to animals with intact AT2 receptor [17]. Furthermore, it has recently been reported that AT2 receptor blockade exacerbated interstitial fibrosis in unilateral ureteral obstruction model rats [18]. Since AT2 receptors do exist in adult kidneys, it is possible that the blockade of AT1 receptor in the remnant kidney elevates endogenous AII and leads to the activation of AT2 receptors, which could further ameliorate interstitial fibrosis. In contrast, monocyte/macrophage infiltration was inhibited by ACI, but not by AT1 receptor antagonist [19]. Thus, ACI and AT1 receptor antagonist may exert additive effects, as recently suggested in terms of proteinuria in patients with IgA nephropathy [20].

Anti-fibrotic agent as a new class of drugs

In the past, strategies to prevent extracellular matrix accumulation in the interstitium, as well as in glomeruli, mainly aimed at blocking the action or activation of TGFß [12]. The efficacy of this approach is supported by the results of in vivo [21] and in vitro [22] studies. As discussed before, transformation of epithelial cells or mesenchymal cells to active fibroblasts may be another target step for the prevention of interstitial fibrosis in the future. In addition, synthesis of extracellular matrix and accumulation of matrix proteins may be targets for therapy.

Pirfenidone (PFD) is a recently developed antifibrotic agent that prevents and even reverses extracellular matrix accumulation, as shown in experimental pulmonary fibrosis [23] and peritoneal sclerosis [24]. Furthermore, recent clinical data suggested that PFD not only improved the survival rate, but also restored pulmonary function in patients with end-stage pulmonary fibrosis [25]. In addition, the absence of PFD toxicity suggests that this agent does not affect normal turnover of extracellular matrix.

We examined the efficacy of PFD on progressive renal disease in rat models of renal damage, i.e. the Thy1 glomerulonephritis induced by a monoclonal anti-Thy-1 antibody [26] and the model of subtotal nephrectomy [27]. In these models, PFD not only prevented the progression of sclerotic glomerular lesions, but also ameliorated interstitial lesions and decreased collagen accumulation in the kidney. We next examined the effect of PFD in the rat model of unilateral ureteral obstruction, a well-characterized model of tubulointerstitial fibrosis. As reported recently, PFD not only attenuated interstitial changes and collagen accumulation, but also induced better recovery of renal function after release of obstruction [28]. We conclude that PFD is promising as a novel agent for the prevention and treatment of interstitial fibrosis and glomerulosclerosis.

At the moment, the mechanism underlying the antifibrotic action of PFD is poorly understood. Suppression of increased TGF-ß and inhibition of its effects is certainly one possibility, as shown in the remnant and post-obstruction models [27,28]. Inhibition of TNF-{alpha} production by PFD was shown in vitro (unpublished data); this may be another possibility. TNF-{alpha} is responsible for chronic inflammation that precedes extracellular matrix accumulation. Furthermore, overexpression of TNF-{alpha} in the lung results in pulmonary fibrosis, as reported recently [29]. Nevertheless, the most interesting property of PFD is that this agent may even reverse fibrosis. For instance, improvement of pulmonary function was seen in patients with end-stage pulmonary fibrosis [25].

A dynamic balance between synthesis and degradation determines the amount of extracellular matrix. Degradation of matrix protein is regulated by two major systems, i.e. the matrix metalloproteinase (MMP)/tissue inhibitor of MMP (TIMP) system on the one hand, and plasminogen activator/plasmin system on the other [30]. In several models of renal disease matrix accumulation was associated not only with increased synthesis, but also with diminished breakdown as suggested by suppression of MMP and/or activation of TIMP [31,32]. For the reversal of fibrosis, degradation of accumulated matrix should be enhanced. This can be achieved in principle by activation of MMP or suppression of TIMP. Currently, there is no drug available which has such actions.

It may be an attractive idea to develop a new category of drugs which activate matrix degrading system [33]. Whether PFD belongs to this category of drug remains to be clarified. This would then constitute a new pharmacological approach to fibrosis.

Prospects

Prevention and reversal of interstitial fibrosis is one of the key strategies for the treatment of progressive renal disease. Since most renal diseases are diagnosed only at a time when extracellular matrix has already accumulated, strategies to reverse existing fibrosis are necessary. We are optimistic that further studies at the cellular and molecular levels will lead to a breakthrough that will enable us to reverse this abnormality in the near future.

References

  1. Strutz F, Muller GA. On the progression of chronic renal disease. Nephron 1995; 69: 371–379[ISI][Medline]
  2. Bohle A, Muller GA, Wehrmann M, Mackensen-Haen S, Xiao JC. Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies, and chronic interstitial nephritides. Kidney Int 1996; 54: S2–9
  3. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 1981; 241: F85–93[Abstract/Free Full Text]
  4. Eddy AA. Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 1996; 7: 2495–2508[Abstract]
  5. Inagami T. Molecular biology and signaling of angiotensin receptors: An overview. J Am Soc Nephrol 1999; 10 [Suppl. 11]: S2–7[ISI][Medline]
  6. Chung O, Kuhl H, Stoll M, Unger T. Physiological and pharmacological implications of AT1 versus AT2 receptors. Kidney Int 1998; 54: S95–99[ISI]
  7. Lapinski R, Perico N, Remuzzi A, Sangalli F, Benigni A, Remuzzi G. Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney. J Am Soc Nephrol 1996; 7: 653–660[Abstract]
  8. Nahas AME, Muchaneta-Kubara EC, Zhang G, Adam A, Goumenos D. Phenotypic modulation of renal cells during experimental and clinical renal scarring. Kidney Int 1996; 49: S23–27[ISI]
  9. Struz F, Okada H, Lo CW et al. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 1995; 130: 393–405[Abstract]
  10. Okada H, Danoff TM, Kalluri R, Neilson EG. Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 1997; 273: F563–574[Abstract/Free Full Text]
  11. Ng YY, Huang TP, Yang WC et al. Tubular epithelial–myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int 1998; 54: 864–876[ISI][Medline]
  12. Border WA, Noble NA. Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension 1998; 31: 181–188[Abstract/Free Full Text]
  13. Noda M, Matsuo T, Fukuda R et al. Effects of candesartan cilexetil (TCV-116) in rats with chronic renal failure. Kidney Int (in press)
  14. Ozono R, Wang ZQ, Moore AF, Inagami T, Siragy MM, Carey RM. Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney. Hypertension 1997; 30: 1238–1246[Abstract/Free Full Text]
  15. Arima S, Endo Y, Yaoita H et al. Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole. J Clin Invest 1997; 100: 2816–2823[Abstract/Free Full Text]
  16. Kurokawa K. Effect of candesartan on the proteinuria of chronic glomerulonephritis. J Hum Hypertens 1999; 13 [Suppl 1]: S57–60[ISI][Medline]
  17. Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int 1998; 53: 937–944[ISI][Medline]
  18. Morrissey JJ, Klahr S. Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. Am J Physiol 1999; 276: F39–45[Abstract/Free Full Text]
  19. Ishidoya S, Morrissey R, McCracken R, Klahr S. Angiotensin II receptor antagonist ameliorates renal tubular interstitial fibrosis caused by unilateral obstruction. Kidney Int 1995; 47: 1285–1294[ISI][Medline]
  20. Russo D, Pisani A, Balleta MM et al. Additive antiproteinuric effect of converting enzyme inhibitor and Losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 1999; 33: 851–856[ISI][Medline]
  21. Isaka Y, Akagi Y, Ando Y et al. Gene therapy by transforming growth factor-beta receptor IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 1999; 55: 465–475[ISI][Medline]
  22. Hori Y, Katoh T, Hirakata M et al. Anti-latent transforming growth factor-ß binding protein-1 antibody or synthetic oligopeptides inhibit extracellular matrix expression induced by stretch in cultured rat mesangial cells. Kidney Int 1998; 53: 1616–1625[ISI][Medline]
  23. Iyer SN, Wild JS, Schiedt MJ, Hyde DM, Margolin SB, Giri SN. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med 1995; 125: 779–785[ISI][Medline]
  24. Suga H, Teraoka S, Oka K et al. Preventive effect of pirfenidone against experimental sclerosing peritonitis in rats. Exp Toxic Pathol 1995; 47: 287–292[ISI][Medline]
  25. Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone. Am J Respir Crit Care Med 1999; 159: 1061–1069[Abstract/Free Full Text]
  26. Shimizu F, Fukagawa M, Yamauchi S et al. Pirfenidone prevents the progression of irreversible glomerular sclerosis lesions in rats. Nephrology 1997; 3: 315–322[ISI]
  27. Shimizu T, Fukagawa M, Kuroda T et al. Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partial nephrectomy. Kidney Int 1997; 52 [Suppl. 63]: S239–243
  28. Shimizu T, Kuroda T, Hata T, Fukagawa M, Margolin SB, Kurokawa K. Pirfenidone improves renal function and fibrosis in the post-obstructed kidney. Kidney Int 1998; 54: 99–109[ISI][Medline]
  29. Miyazaki Y, Araki K, Vesin C et al. Expression of tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. J Clin Invest 1995; 96: 250–259[ISI][Medline]
  30. Jones CI. Matrix degradation in renal disease. Nephrology 1996; 2: 13–23[ISI]
  31. Duymelinck C, Deng JT, Dauwe SE, De Broe ME, Verpooten GA. Inhibition of the matrix metalloproteinase system in a rat model of chronic cyclosporine nephropathy. Kidney Int 1998; 54: 804–818[ISI][Medline]
  32. Gonzalez Avila G, Iturria C, Vadillo Ortega F, Ovalle C, Monta M. Changes in matrix metalloproteinase during the evolution of interstitial renal fibrosis in a rat experimental model. Pathobiology 1998; 66: 196–204[ISI][Medline]
  33. Heidland A, Sebekova K, Paczek L, Teschner M, Dammrich J, Gaciong Z. Renal fibrosis: Role of impaired proteolysis and potential therapeutic strategies. Kidney Int 1997; 62 [Suppl. 62]: S32–35




This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (11)
Disclaimer
Request Permissions
Google Scholar
Articles by Fukagawa, M.
Articles by Kurokawa, K.
PubMed
PubMed Citation
Articles by Fukagawa, M.
Articles by Kurokawa, K.